Full text data of PPARGC1B
PPARGC1B
(PERC, PGC1, PGC1B, PPARGC1)
[Confidence: low (only semi-automatic identification from reviews)]
Peroxisome proliferator-activated receptor gamma coactivator 1-beta; PGC-1-beta; PPAR-gamma coactivator 1-beta; PPARGC-1-beta (PGC-1-related estrogen receptor alpha coactivator)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Peroxisome proliferator-activated receptor gamma coactivator 1-beta; PGC-1-beta; PPAR-gamma coactivator 1-beta; PPARGC-1-beta (PGC-1-related estrogen receptor alpha coactivator)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q86YN6
ID PRGC2_HUMAN Reviewed; 1023 AA.
AC Q86YN6; A2RUM8; A2RUN0; B3KVW0; Q86YN3; Q86YN4; Q86YN5; Q8N1N9;
read moreAC Q8TDE4; Q8TDE5;
DT 13-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 97.
DE RecName: Full=Peroxisome proliferator-activated receptor gamma coactivator 1-beta;
DE Short=PGC-1-beta;
DE Short=PPAR-gamma coactivator 1-beta;
DE Short=PPARGC-1-beta;
DE AltName: Full=PGC-1-related estrogen receptor alpha coactivator;
GN Name=PPARGC1B; Synonyms=PERC, PGC1, PGC1B, PPARGC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 5), SUBCELLULAR LOCATION,
RP MOTIF, TISSUE SPECIFICITY, MUTAGENESIS OF 92-LEU--LEU-96;
RP 155-LEU--LEU-160 AND 343-LEU--LEU-347, INTERACTION WITH ESR1, AND
RP FUNCTION.
RX PubMed=11854298; DOI=10.1074/jbc.M201134200;
RA Kressler D., Schreiber S.N., Knutti D., Kralli A.;
RT "The PGC-1-related protein PERC is a selective coactivator of estrogen
RT receptor alpha.";
RL J. Biol. Chem. 277:13918-13925(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), TISSUE
RP SPECIFICITY, FUNCTION, AND VARIANT GLN-265.
RX PubMed=12678921; DOI=10.1042/BJ20030200;
RA Meirhaeghe A., Crowley V., Lenaghan C., Lelliott C., Green K.,
RA Stewart A., Hart K., Schinner S., Sethi J.K., Yeo G., Brand M.D.,
RA Cortright R.N., O'Rahilly S., Montague C., Vidal-Puig A.J.;
RT "Characterization of the human, mouse and rat PGC1 beta (peroxisome-
RT proliferator-activated receptor-gamma co-activator 1 beta) gene in
RT vitro and in vivo.";
RL Biochem. J. 373:155-165(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 6).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP SER-292.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP INDUCTION.
RX PubMed=12832613; DOI=10.1073/pnas.1032913100;
RA Patti M.E., Butte A.J., Crunkhorn S., Cusi K., Berria R., Kashyap S.,
RA Miyazaki Y., Kohane I., Costello M., Saccone R., Landaker E.J.,
RA Goldfine A.B., Mun E., DeFronzo R., Finlayson J., Kahn C.R.,
RA Mandarino L.J.;
RT "Coordinated reduction of genes of oxidative metabolism in humans with
RT insulin resistance and diabetes: potential role of PGC1 and NRF1.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:8466-8471(2003).
RN [8]
RP FUNCTION, AND INDUCTION BY INSULIN AND AGING.
RX PubMed=15546003; DOI=10.1172/JCI21889;
RA Ling C., Poulsen P., Carlsson E., Ridderstrale M., Almgren P.,
RA Wojtaszewski J., Beck-Nielsen H., Groop L., Vaag A.;
RT "Multiple environmental and genetic factors influence skeletal muscle
RT PGC-1alpha and PGC-1beta gene expression in twins.";
RL J. Clin. Invest. 114:1518-1526(2004).
RN [9]
RP POLYMORPHISM, AND VARIANTS PRO-203; ILE-279 AND SER-292.
RX PubMed=15863669; DOI=10.1136/jmg.2004.026278;
RA Andersen G., Wegner L., Yanagisawa K., Rose C.S., Lin J., Gluemer C.,
RA Drivsholm T., Borch-Johnsen K., Jorgensen T., Hansen T.,
RA Spiegelman B.M., Pedersen O.;
RT "Evidence of an association between genetic variation of the
RT coactivator PGC-1beta and obesity.";
RL J. Med. Genet. 42:402-407(2005).
RN [10]
RP REGULATION BY FATTY ACIDS.
RX PubMed=16132959; DOI=10.1007/s00125-005-1895-z;
RA Staiger H., Staiger K., Haas C., Weisser M., Machicao F.,
RA Haering H.-U.;
RT "Fatty acid-induced differential regulation of the genes encoding
RT peroxisome proliferator-activated receptor-gamma coactivator-1alpha
RT and -1beta in human skeletal muscle cells that have been
RT differentiated in vitro.";
RL Diabetologia 48:2115-2118(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-524, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
CC -!- FUNCTION: Plays a role of stimulator of transcription factors and
CC nuclear receptors activities. Activates transcritional activity of
CC estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and
CC glucocorticoid receptor in the presence of glucocorticoids. May
CC play a role in constitutive non-adrenergic-mediated mitochondrial
CC biogenesis as suggested by increased basal oxygen consumption and
CC mitochondrial number when overexpressed. May be involved in fat
CC oxidation and non-oxidative glucose metabolism and in the
CC regulation of energy expenditure.
CC -!- SUBUNIT: Interacts with hepatocyte nuclear factor 4-alpha/HNF4A,
CC Sterol regulatory binding transcription factor 1/SREBF1, PPAR-
CC alpha/PPARA, thyroid hormone receptor beta/THRB and host cell
CC factor/HCFC1. Interacts with estrogen-related receptor gamma/ESRRG
CC and alpha/ESRRA. Interacts with PRDM16 (By similarity). Interacts
CC with estrogen receptor alpha/ESR1.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=PGC1beta-1a;
CC IsoId=Q86YN6-1; Sequence=Displayed;
CC Name=2; Synonyms=PGC1beta-2a;
CC IsoId=Q86YN6-2; Sequence=VSP_019299;
CC Name=3; Synonyms=PGC1beta-1b;
CC IsoId=Q86YN6-3; Sequence=VSP_019301;
CC Name=4; Synonyms=PGC1beta-2b;
CC IsoId=Q86YN6-4; Sequence=VSP_019299, VSP_019301;
CC Name=5; Synonyms=PERC-s;
CC IsoId=Q86YN6-5; Sequence=VSP_019300;
CC Note=Lacks LXXLL motif 1 and has a reduced ability to enhance
CC the hormone-dependent activity of estrogen receptor alpha;
CC Name=6;
CC IsoId=Q86YN6-6; Sequence=VSP_043374, VSP_019300;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous with higher expression in heart,
CC brain and skeletal muscle.
CC -!- INDUCTION: Repressed by saturated fatty acids such as palmitate
CC and stearate in skeletal muscle cells. Induced by insulin and
CC reduced by aging in skeletal muscle biopsies. Down-regulated in
CC type 2 diabetes mellitus subjects as well as in pre-diabetics.
CC -!- DOMAIN: Contains 2 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which are
CC usually required for the association with nuclear receptors (By
CC similarity).
CC -!- POLYMORPHISM: Variation of PPARGC1B may contribute to the
CC pathogenesis of obesity, with a widespread Ala-203 allele being a
CC risk factor for the development of this common disorders.
CC -!- SIMILARITY: Contains 1 RRM (RNA recognition motif) domain.
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DR EMBL; AF468496; AAL78633.1; -; mRNA.
DR EMBL; AF468497; AAL78634.1; -; mRNA.
DR EMBL; AY188947; AAO40022.1; -; mRNA.
DR EMBL; AY188948; AAO40023.1; -; mRNA.
DR EMBL; AY188949; AAO40024.1; -; mRNA.
DR EMBL; AY188950; AAO40025.1; -; mRNA.
DR EMBL; AK095391; BAC04541.1; -; mRNA.
DR EMBL; AK123614; BAG53922.1; -; mRNA.
DR EMBL; AC008545; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022100; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61759.1; -; Genomic_DNA.
DR EMBL; BC132971; AAI32972.1; -; mRNA.
DR EMBL; BC132973; AAI32974.1; -; mRNA.
DR RefSeq; NP_001166169.1; NM_001172698.1.
DR RefSeq; NP_001166170.1; NM_001172699.1.
DR RefSeq; NP_573570.3; NM_133263.3.
DR RefSeq; XP_005268429.1; XM_005268372.1.
DR UniGene; Hs.483816; -.
DR PDB; 3SP6; X-ray; 2.21 A; B=153-163.
DR PDBsum; 3SP6; -.
DR ProteinModelPortal; Q86YN6; -.
DR SMR; Q86YN6; 900-992.
DR PhosphoSite; Q86YN6; -.
DR DMDM; 116242724; -.
DR PaxDb; Q86YN6; -.
DR PRIDE; Q86YN6; -.
DR Ensembl; ENST00000309241; ENSP00000312649; ENSG00000155846.
DR Ensembl; ENST00000360453; ENSP00000353638; ENSG00000155846.
DR Ensembl; ENST00000394320; ENSP00000377855; ENSG00000155846.
DR Ensembl; ENST00000403750; ENSP00000384403; ENSG00000155846.
DR GeneID; 133522; -.
DR KEGG; hsa:133522; -.
DR UCSC; uc003lrc.3; human.
DR CTD; 133522; -.
DR GeneCards; GC05P149109; -.
DR HGNC; HGNC:30022; PPARGC1B.
DR MIM; 608886; gene.
DR neXtProt; NX_Q86YN6; -.
DR PharmGKB; PA134953410; -.
DR eggNOG; NOG87590; -.
DR HOGENOM; HOG000236356; -.
DR HOVERGEN; HBG080730; -.
DR InParanoid; Q86YN6; -.
DR OMA; CESGCGD; -.
DR OrthoDB; EOG7S4X5H; -.
DR PhylomeDB; Q86YN6; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; Q86YN6; -.
DR GeneWiki; PPARGC1B; -.
DR GenomeRNAi; 133522; -.
DR NextBio; 83227; -.
DR PRO; PR:Q86YN6; -.
DR Bgee; Q86YN6; -.
DR CleanEx; HS_PPARGC1B; -.
DR Genevestigator; Q86YN6; -.
DR GO; GO:0016592; C:mediator complex; IDA:UniProtKB.
DR GO; GO:0030331; F:estrogen receptor binding; IDA:UniProtKB.
DR GO; GO:0030374; F:ligand-dependent nuclear receptor transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0030546; F:receptor activator activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; NAS:UniProtKB.
DR GO; GO:0001104; F:RNA polymerase II transcription cofactor activity; IDA:UniProtKB.
DR GO; GO:0007015; P:actin filament organization; IEA:Ensembl.
DR GO; GO:0060346; P:bone trabecula formation; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; IEA:Ensembl.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IEA:Ensembl.
DR GO; GO:0001503; P:ossification; IEA:Ensembl.
DR GO; GO:0010694; P:positive regulation of alkaline phosphatase activity; IEA:Ensembl.
DR GO; GO:0045780; P:positive regulation of bone resorption; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006390; P:transcription from mitochondrial promoter; IEA:Ensembl.
DR Gene3D; 3.30.70.330; -; 1.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR Pfam; PF00076; RRM_1; 1.
DR SMART; SM00360; RRM; 1.
DR PROSITE; PS50102; RRM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Complete proteome;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW RNA-binding; Transcription; Transcription regulation.
FT CHAIN 1 1023 Peroxisome proliferator-activated
FT receptor gamma coactivator 1-beta.
FT /FTId=PRO_0000240158.
FT DOMAIN 902 976 RRM.
FT REGION 1 91 Abolishes DNA transcriptional activity
FT when missing.
FT MOTIF 156 160 LXXLL motif 1.
FT MOTIF 343 347 LXXLL motif 2.
FT MOTIF 691 694 HCFC1-binding-motif (HBM).
FT COMPBIAS 430 450 Glu-rich.
FT COMPBIAS 772 823 Glu-rich.
FT MOD_RES 524 524 Phosphoserine.
FT VAR_SEQ 1 26 MAGNDCGALLDEELSSFFLNYLADTQ -> MGVYK (in
FT isoform 2 and isoform 4).
FT /FTId=VSP_019299.
FT VAR_SEQ 1 26 MAGNDCGALLDEELSSFFLNYLADTQ -> M (in
FT isoform 6).
FT /FTId=VSP_043374.
FT VAR_SEQ 156 194 Missing (in isoform 5 and isoform 6).
FT /FTId=VSP_019300.
FT VAR_SEQ 991 1023 DSNSEEALPASGKSKYEAMDFDSLLKEAQQSLH -> GKPL
FT KPSHSLVRLKAWEAVPSLNKTQS (in isoform 3 and
FT isoform 4).
FT /FTId=VSP_019301.
FT VARIANT 203 203 A -> P (in dbSNP:rs7732671).
FT /FTId=VAR_026698.
FT VARIANT 265 265 R -> Q (in dbSNP:rs45520937).
FT /FTId=VAR_026699.
FT VARIANT 279 279 V -> I (in dbSNP:rs17572019).
FT /FTId=VAR_026700.
FT VARIANT 292 292 R -> S (in dbSNP:rs11959820).
FT /FTId=VAR_026701.
FT MUTAGEN 92 96 LLAEL->AAAEA: Reduces DNA transcriptional
FT activity.
FT MUTAGEN 155 160 LLQKLL->AAQKAA: Reduces interaction and
FT activation of ESR1. Loss of interaction
FT and activation of ESR1; when associated
FT with 343-AREAA-347.
FT MUTAGEN 343 347 LRELL->AREAA: Reduces interaction and
FT activation of ESR1. Loss of interaction
FT and activation of ESR1; when associated
FT with 155-AAQKAA-160.
FT CONFLICT 558 558 E -> G (in Ref. 3; BAC04541).
FT HELIX 155 162
SQ SEQUENCE 1023 AA; 113222 MW; DC37FCDE4D3CD239 CRC64;
MAGNDCGALL DEELSSFFLN YLADTQGGGS GEEQLYADFP ELDLSQLDAS DFDSATCFGE
LQWCPENSET EPNQYSPDDS ELFQIDSENE ALLAELTKTL DDIPEDDVGL AAFPALDGGD
ALSCTSASPA PSSAPPSPAP EKPSAPAPEV DELSLLQKLL LATSYPTSSS DTQKEGTAWR
QAGLRSKSQR PCVKADSTQD KKAPMMQSQS RSCTELHKHL TSAQCCLQDR GLQPPCLQSP
RLPAKEDKEP GEDCPSPQPA PASPRDSLAL GRADPGAPVS QEDMQAMVQL IRYMHTYCLP
QRKLPPQTPE PLPKACSNPS QQVRSRPWSR HHSKASWAEF SILRELLAQD VLCDVSKPYR
LATPVYASLT PRSRPRPPKD SQASPGRPSS VEEVRIAASP KSTGPRPSLR PLRLEVKREV
RRPARLQQQE EEDEEEEEEE EEEEKEEEEE WGRKRPGRGL PWTKLGRKLE SSVCPVRRSR
RLNPELGPWL TFADEPLVPS EPQGALPSLC LAPKAYDVER ELGSPTDEDS GQDQQLLRGP
QIPALESPCE SGCGDMDEDP SCPQLPPRDS PRCLMLALSQ SDPTFGKKSF EQTLTVELCG
TAGLTPPTTP PYKPTEEDPF KPDIKHSLGK EIALSLPSPE GLSLKATPGA AHKLPKKHPE
RSELLSHLRH ATAQPASQAG QKRPFSCSFG DHDYCQVLRP EGVLQRKVLR SWEPSGVHLE
DWPQQGAPWA EAQAPGREED RSCDAGAPPK DSTLLRDHEI RASLTKHFGL LETALEEEDL
ASCKSPEYDT VFEDSSSSSG ESSFLPEEEE EEGEEEEEDD EEEDSGVSPT CSDHCPYQSP
PSKANRQLCS RSRSSSGSSP CHSWSPATRR NFRCESRGPC SDRTPSIRHA RKRREKAIGE
GRVVYIQNLS SDMSSRELKR RFEVFGEIEE CEVLTRNRRG EKYGFITYRC SEHAALSLTK
GAALRKRNEP SFQLSYGGLR HFCWPRYTDY DSNSEEALPA SGKSKYEAMD FDSLLKEAQQ
SLH
//
ID PRGC2_HUMAN Reviewed; 1023 AA.
AC Q86YN6; A2RUM8; A2RUN0; B3KVW0; Q86YN3; Q86YN4; Q86YN5; Q8N1N9;
read moreAC Q8TDE4; Q8TDE5;
DT 13-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 97.
DE RecName: Full=Peroxisome proliferator-activated receptor gamma coactivator 1-beta;
DE Short=PGC-1-beta;
DE Short=PPAR-gamma coactivator 1-beta;
DE Short=PPARGC-1-beta;
DE AltName: Full=PGC-1-related estrogen receptor alpha coactivator;
GN Name=PPARGC1B; Synonyms=PERC, PGC1, PGC1B, PPARGC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 5), SUBCELLULAR LOCATION,
RP MOTIF, TISSUE SPECIFICITY, MUTAGENESIS OF 92-LEU--LEU-96;
RP 155-LEU--LEU-160 AND 343-LEU--LEU-347, INTERACTION WITH ESR1, AND
RP FUNCTION.
RX PubMed=11854298; DOI=10.1074/jbc.M201134200;
RA Kressler D., Schreiber S.N., Knutti D., Kralli A.;
RT "The PGC-1-related protein PERC is a selective coactivator of estrogen
RT receptor alpha.";
RL J. Biol. Chem. 277:13918-13925(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), TISSUE
RP SPECIFICITY, FUNCTION, AND VARIANT GLN-265.
RX PubMed=12678921; DOI=10.1042/BJ20030200;
RA Meirhaeghe A., Crowley V., Lenaghan C., Lelliott C., Green K.,
RA Stewart A., Hart K., Schinner S., Sethi J.K., Yeo G., Brand M.D.,
RA Cortright R.N., O'Rahilly S., Montague C., Vidal-Puig A.J.;
RT "Characterization of the human, mouse and rat PGC1 beta (peroxisome-
RT proliferator-activated receptor-gamma co-activator 1 beta) gene in
RT vitro and in vivo.";
RL Biochem. J. 373:155-165(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 6).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP SER-292.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP INDUCTION.
RX PubMed=12832613; DOI=10.1073/pnas.1032913100;
RA Patti M.E., Butte A.J., Crunkhorn S., Cusi K., Berria R., Kashyap S.,
RA Miyazaki Y., Kohane I., Costello M., Saccone R., Landaker E.J.,
RA Goldfine A.B., Mun E., DeFronzo R., Finlayson J., Kahn C.R.,
RA Mandarino L.J.;
RT "Coordinated reduction of genes of oxidative metabolism in humans with
RT insulin resistance and diabetes: potential role of PGC1 and NRF1.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:8466-8471(2003).
RN [8]
RP FUNCTION, AND INDUCTION BY INSULIN AND AGING.
RX PubMed=15546003; DOI=10.1172/JCI21889;
RA Ling C., Poulsen P., Carlsson E., Ridderstrale M., Almgren P.,
RA Wojtaszewski J., Beck-Nielsen H., Groop L., Vaag A.;
RT "Multiple environmental and genetic factors influence skeletal muscle
RT PGC-1alpha and PGC-1beta gene expression in twins.";
RL J. Clin. Invest. 114:1518-1526(2004).
RN [9]
RP POLYMORPHISM, AND VARIANTS PRO-203; ILE-279 AND SER-292.
RX PubMed=15863669; DOI=10.1136/jmg.2004.026278;
RA Andersen G., Wegner L., Yanagisawa K., Rose C.S., Lin J., Gluemer C.,
RA Drivsholm T., Borch-Johnsen K., Jorgensen T., Hansen T.,
RA Spiegelman B.M., Pedersen O.;
RT "Evidence of an association between genetic variation of the
RT coactivator PGC-1beta and obesity.";
RL J. Med. Genet. 42:402-407(2005).
RN [10]
RP REGULATION BY FATTY ACIDS.
RX PubMed=16132959; DOI=10.1007/s00125-005-1895-z;
RA Staiger H., Staiger K., Haas C., Weisser M., Machicao F.,
RA Haering H.-U.;
RT "Fatty acid-induced differential regulation of the genes encoding
RT peroxisome proliferator-activated receptor-gamma coactivator-1alpha
RT and -1beta in human skeletal muscle cells that have been
RT differentiated in vitro.";
RL Diabetologia 48:2115-2118(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-524, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
CC -!- FUNCTION: Plays a role of stimulator of transcription factors and
CC nuclear receptors activities. Activates transcritional activity of
CC estrogen receptor alpha, nuclear respiratory factor 1 (NRF1) and
CC glucocorticoid receptor in the presence of glucocorticoids. May
CC play a role in constitutive non-adrenergic-mediated mitochondrial
CC biogenesis as suggested by increased basal oxygen consumption and
CC mitochondrial number when overexpressed. May be involved in fat
CC oxidation and non-oxidative glucose metabolism and in the
CC regulation of energy expenditure.
CC -!- SUBUNIT: Interacts with hepatocyte nuclear factor 4-alpha/HNF4A,
CC Sterol regulatory binding transcription factor 1/SREBF1, PPAR-
CC alpha/PPARA, thyroid hormone receptor beta/THRB and host cell
CC factor/HCFC1. Interacts with estrogen-related receptor gamma/ESRRG
CC and alpha/ESRRA. Interacts with PRDM16 (By similarity). Interacts
CC with estrogen receptor alpha/ESR1.
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=PGC1beta-1a;
CC IsoId=Q86YN6-1; Sequence=Displayed;
CC Name=2; Synonyms=PGC1beta-2a;
CC IsoId=Q86YN6-2; Sequence=VSP_019299;
CC Name=3; Synonyms=PGC1beta-1b;
CC IsoId=Q86YN6-3; Sequence=VSP_019301;
CC Name=4; Synonyms=PGC1beta-2b;
CC IsoId=Q86YN6-4; Sequence=VSP_019299, VSP_019301;
CC Name=5; Synonyms=PERC-s;
CC IsoId=Q86YN6-5; Sequence=VSP_019300;
CC Note=Lacks LXXLL motif 1 and has a reduced ability to enhance
CC the hormone-dependent activity of estrogen receptor alpha;
CC Name=6;
CC IsoId=Q86YN6-6; Sequence=VSP_043374, VSP_019300;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous with higher expression in heart,
CC brain and skeletal muscle.
CC -!- INDUCTION: Repressed by saturated fatty acids such as palmitate
CC and stearate in skeletal muscle cells. Induced by insulin and
CC reduced by aging in skeletal muscle biopsies. Down-regulated in
CC type 2 diabetes mellitus subjects as well as in pre-diabetics.
CC -!- DOMAIN: Contains 2 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which are
CC usually required for the association with nuclear receptors (By
CC similarity).
CC -!- POLYMORPHISM: Variation of PPARGC1B may contribute to the
CC pathogenesis of obesity, with a widespread Ala-203 allele being a
CC risk factor for the development of this common disorders.
CC -!- SIMILARITY: Contains 1 RRM (RNA recognition motif) domain.
CC -----------------------------------------------------------------------
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DR EMBL; AF468496; AAL78633.1; -; mRNA.
DR EMBL; AF468497; AAL78634.1; -; mRNA.
DR EMBL; AY188947; AAO40022.1; -; mRNA.
DR EMBL; AY188948; AAO40023.1; -; mRNA.
DR EMBL; AY188949; AAO40024.1; -; mRNA.
DR EMBL; AY188950; AAO40025.1; -; mRNA.
DR EMBL; AK095391; BAC04541.1; -; mRNA.
DR EMBL; AK123614; BAG53922.1; -; mRNA.
DR EMBL; AC008545; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022100; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61759.1; -; Genomic_DNA.
DR EMBL; BC132971; AAI32972.1; -; mRNA.
DR EMBL; BC132973; AAI32974.1; -; mRNA.
DR RefSeq; NP_001166169.1; NM_001172698.1.
DR RefSeq; NP_001166170.1; NM_001172699.1.
DR RefSeq; NP_573570.3; NM_133263.3.
DR RefSeq; XP_005268429.1; XM_005268372.1.
DR UniGene; Hs.483816; -.
DR PDB; 3SP6; X-ray; 2.21 A; B=153-163.
DR PDBsum; 3SP6; -.
DR ProteinModelPortal; Q86YN6; -.
DR SMR; Q86YN6; 900-992.
DR PhosphoSite; Q86YN6; -.
DR DMDM; 116242724; -.
DR PaxDb; Q86YN6; -.
DR PRIDE; Q86YN6; -.
DR Ensembl; ENST00000309241; ENSP00000312649; ENSG00000155846.
DR Ensembl; ENST00000360453; ENSP00000353638; ENSG00000155846.
DR Ensembl; ENST00000394320; ENSP00000377855; ENSG00000155846.
DR Ensembl; ENST00000403750; ENSP00000384403; ENSG00000155846.
DR GeneID; 133522; -.
DR KEGG; hsa:133522; -.
DR UCSC; uc003lrc.3; human.
DR CTD; 133522; -.
DR GeneCards; GC05P149109; -.
DR HGNC; HGNC:30022; PPARGC1B.
DR MIM; 608886; gene.
DR neXtProt; NX_Q86YN6; -.
DR PharmGKB; PA134953410; -.
DR eggNOG; NOG87590; -.
DR HOGENOM; HOG000236356; -.
DR HOVERGEN; HBG080730; -.
DR InParanoid; Q86YN6; -.
DR OMA; CESGCGD; -.
DR OrthoDB; EOG7S4X5H; -.
DR PhylomeDB; Q86YN6; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; Q86YN6; -.
DR GeneWiki; PPARGC1B; -.
DR GenomeRNAi; 133522; -.
DR NextBio; 83227; -.
DR PRO; PR:Q86YN6; -.
DR Bgee; Q86YN6; -.
DR CleanEx; HS_PPARGC1B; -.
DR Genevestigator; Q86YN6; -.
DR GO; GO:0016592; C:mediator complex; IDA:UniProtKB.
DR GO; GO:0030331; F:estrogen receptor binding; IDA:UniProtKB.
DR GO; GO:0030374; F:ligand-dependent nuclear receptor transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0030546; F:receptor activator activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; NAS:UniProtKB.
DR GO; GO:0001104; F:RNA polymerase II transcription cofactor activity; IDA:UniProtKB.
DR GO; GO:0007015; P:actin filament organization; IEA:Ensembl.
DR GO; GO:0060346; P:bone trabecula formation; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; IEA:Ensembl.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IEA:Ensembl.
DR GO; GO:0001503; P:ossification; IEA:Ensembl.
DR GO; GO:0010694; P:positive regulation of alkaline phosphatase activity; IEA:Ensembl.
DR GO; GO:0045780; P:positive regulation of bone resorption; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006390; P:transcription from mitochondrial promoter; IEA:Ensembl.
DR Gene3D; 3.30.70.330; -; 1.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR Pfam; PF00076; RRM_1; 1.
DR SMART; SM00360; RRM; 1.
DR PROSITE; PS50102; RRM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Complete proteome;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW RNA-binding; Transcription; Transcription regulation.
FT CHAIN 1 1023 Peroxisome proliferator-activated
FT receptor gamma coactivator 1-beta.
FT /FTId=PRO_0000240158.
FT DOMAIN 902 976 RRM.
FT REGION 1 91 Abolishes DNA transcriptional activity
FT when missing.
FT MOTIF 156 160 LXXLL motif 1.
FT MOTIF 343 347 LXXLL motif 2.
FT MOTIF 691 694 HCFC1-binding-motif (HBM).
FT COMPBIAS 430 450 Glu-rich.
FT COMPBIAS 772 823 Glu-rich.
FT MOD_RES 524 524 Phosphoserine.
FT VAR_SEQ 1 26 MAGNDCGALLDEELSSFFLNYLADTQ -> MGVYK (in
FT isoform 2 and isoform 4).
FT /FTId=VSP_019299.
FT VAR_SEQ 1 26 MAGNDCGALLDEELSSFFLNYLADTQ -> M (in
FT isoform 6).
FT /FTId=VSP_043374.
FT VAR_SEQ 156 194 Missing (in isoform 5 and isoform 6).
FT /FTId=VSP_019300.
FT VAR_SEQ 991 1023 DSNSEEALPASGKSKYEAMDFDSLLKEAQQSLH -> GKPL
FT KPSHSLVRLKAWEAVPSLNKTQS (in isoform 3 and
FT isoform 4).
FT /FTId=VSP_019301.
FT VARIANT 203 203 A -> P (in dbSNP:rs7732671).
FT /FTId=VAR_026698.
FT VARIANT 265 265 R -> Q (in dbSNP:rs45520937).
FT /FTId=VAR_026699.
FT VARIANT 279 279 V -> I (in dbSNP:rs17572019).
FT /FTId=VAR_026700.
FT VARIANT 292 292 R -> S (in dbSNP:rs11959820).
FT /FTId=VAR_026701.
FT MUTAGEN 92 96 LLAEL->AAAEA: Reduces DNA transcriptional
FT activity.
FT MUTAGEN 155 160 LLQKLL->AAQKAA: Reduces interaction and
FT activation of ESR1. Loss of interaction
FT and activation of ESR1; when associated
FT with 343-AREAA-347.
FT MUTAGEN 343 347 LRELL->AREAA: Reduces interaction and
FT activation of ESR1. Loss of interaction
FT and activation of ESR1; when associated
FT with 155-AAQKAA-160.
FT CONFLICT 558 558 E -> G (in Ref. 3; BAC04541).
FT HELIX 155 162
SQ SEQUENCE 1023 AA; 113222 MW; DC37FCDE4D3CD239 CRC64;
MAGNDCGALL DEELSSFFLN YLADTQGGGS GEEQLYADFP ELDLSQLDAS DFDSATCFGE
LQWCPENSET EPNQYSPDDS ELFQIDSENE ALLAELTKTL DDIPEDDVGL AAFPALDGGD
ALSCTSASPA PSSAPPSPAP EKPSAPAPEV DELSLLQKLL LATSYPTSSS DTQKEGTAWR
QAGLRSKSQR PCVKADSTQD KKAPMMQSQS RSCTELHKHL TSAQCCLQDR GLQPPCLQSP
RLPAKEDKEP GEDCPSPQPA PASPRDSLAL GRADPGAPVS QEDMQAMVQL IRYMHTYCLP
QRKLPPQTPE PLPKACSNPS QQVRSRPWSR HHSKASWAEF SILRELLAQD VLCDVSKPYR
LATPVYASLT PRSRPRPPKD SQASPGRPSS VEEVRIAASP KSTGPRPSLR PLRLEVKREV
RRPARLQQQE EEDEEEEEEE EEEEKEEEEE WGRKRPGRGL PWTKLGRKLE SSVCPVRRSR
RLNPELGPWL TFADEPLVPS EPQGALPSLC LAPKAYDVER ELGSPTDEDS GQDQQLLRGP
QIPALESPCE SGCGDMDEDP SCPQLPPRDS PRCLMLALSQ SDPTFGKKSF EQTLTVELCG
TAGLTPPTTP PYKPTEEDPF KPDIKHSLGK EIALSLPSPE GLSLKATPGA AHKLPKKHPE
RSELLSHLRH ATAQPASQAG QKRPFSCSFG DHDYCQVLRP EGVLQRKVLR SWEPSGVHLE
DWPQQGAPWA EAQAPGREED RSCDAGAPPK DSTLLRDHEI RASLTKHFGL LETALEEEDL
ASCKSPEYDT VFEDSSSSSG ESSFLPEEEE EEGEEEEEDD EEEDSGVSPT CSDHCPYQSP
PSKANRQLCS RSRSSSGSSP CHSWSPATRR NFRCESRGPC SDRTPSIRHA RKRREKAIGE
GRVVYIQNLS SDMSSRELKR RFEVFGEIEE CEVLTRNRRG EKYGFITYRC SEHAALSLTK
GAALRKRNEP SFQLSYGGLR HFCWPRYTDY DSNSEEALPA SGKSKYEAMD FDSLLKEAQQ
SLH
//
MIM
608886
*RECORD*
*FIELD* NO
608886
*FIELD* TI
*608886 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, BETA;
PPARGC1B
read more;;PPAR-GAMMA COACTIVATOR 1-BETA; PGC1B;;
PGC1-BETA;;
PGC1-RELATED ESTROGEN RECEPTOR COACTIVATOR; PERC;;
ESTROGEN RECEPTOR-RELATED RECEPTOR LIGAND 1; ERRL1
*FIELD* TX
CLONING
By searching genomic databases with sequence of mouse Pcg1 (PPARGC1A;
604517) as query, Lin et al. (2002) identified a homologous mouse gene,
termed Ppargc1b. Ppargc1b encodes a predicted 1,014-amino acid protein,
and human and mouse PPARGC1B share 70% amino acid sequence identity.
Ppargc1b contains 3 N-terminal LXXLL motifs, 2 glutamic/aspartic
acid-rich acidic domains, a binding site for host cell factor (HCF1;
300019), and a C-terminal RNA recognition motif. Northern blot analysis
showed abundant expression of 9- and 5-kb mouse Ppargc1b transcripts in
brown adipose tissue and heart, and moderate expression in skeletal
muscle, liver, and white adipose tissue.
Kressler et al. (2002) used RT-PCR to amplify full-length human
PPARGC1B, which they referred to as PERC (PGC1-related estrogen receptor
coactivator), from HeLa cells. PPARGC1B encodes a 1,023-amino acid
protein with the same structural features as Ppargc1b, reported by Lin
et al. (2002), and a shorter isoform lacking 39 amino acids (residues
156-194). Immunofluorescence analysis showed that PPARGC1B localizes to
the nucleus. RT-PCR analysis of mouse Ppargc1b showed abundant
expression of the long isoform in heart and skeletal muscle,
intermediate levels in brain, kidney, liver, and adrenal gland, and low
levels in ovary, intestine, and white adipose tissue.
GENE FUNCTION
Lin et al. (2002) showed that murine Ppargc1b shows no change of
expression in brown adipose cells in response to cold exposure, and that
Ppargc1b and Pgc1 have inverse expression levels during brown fat cell
differentiation. However, Ppargc1b expression is increased in liver
during fasting, similar to Pgc1. Immunoprecipitation and reporter
construct activation showed that Ppargc1b interacts with and enhances
the activity of hepatic nuclear factor-4 (600281), peroxisome
proliferator-activated receptor-alpha (170998), and glucocorticoid
receptor (138040). Immunoprecipitation showed HCF1 binds to Ppargc1b and
can increase Ppargc1b transcriptional activity. Ppargc1b is also a
potent regulator of the transcriptional activity of NRF1 (600879), a
central transcription factor in the control of mitochondrial biogenesis.
By transfection of COS-7 cells followed by reporter construct
activation, Kressler et al. (2002) showed that PPARGC1B coactivates
estrogen receptor-alpha (ESR1; 133430). Yeast 2-hybrid analysis showed
ligand-dependent binding of the 2 LXXLL motifs of PPARGC1B to the
ligand-binding domain of ESR1. The PPARGC1B LXXLL motifs and the ESR1
ligand-binding domain are necessary for ESR1 coactivation. An N-terminal
transcriptional activation domain in PPARGC1B is also necessary for ESR1
coactivation. PPARGC1B differed from PPARGC1A in its enhancement of ESR1
activation in various promoter constructs, and PPARGC1B enhanced
ESR1-mediated response to the partial agonist tamoxifen while PPARGC1A
repressed it.
Using cotransfection assays in mammalian cells, Hentschke et al. (2002)
showed that mouse Ppargc1b coactivates estrogen-related receptor-gamma
(ESRRG; 602969). GST pull-down assays showed that Ppargc1b binds ESRRG
in vitro.
Kamei et al. (2003) showed that PGC1B functioned as a ligand for orphan
estrogen receptor-related receptors (ERRs) in vitro. They found that
transgenic mice overexpressing Pgc1b exhibited increased expression of
medium-chain acyl-CoA dehydrogenase (ACADM; 607008), an ERR target and a
pivotal enzyme in mitochondrial beta oxidation in skeletal muscle. As a
result, transgenic mice were hyperphagic, showed elevated energy
expenditure, and were resistant to obesity induced by a high-fat diet or
by genetic abnormality. Kamei et al. (2003) concluded that PGC1B
functions as an ERR ligand and contributes to the control of energy
balance in vivo.
To examine the influence of genetic and environmental factors on the
expression of PPARGC1A and PPARGC1B in human skeletal muscle, Ling et
al. (2004) studied mRNA expression of these transcriptional coactivators
in muscle biopsies from young and elderly monozygotic and dizygotic
twins before and after a hyperinsulinemic euglycemic clamp and found
that insulin increased and aging reduced PPARGC1A and PPARGC1B mRNA
levels. Expression of PPARGC1A in muscle was positively related to
insulin-stimulated glucose uptake and oxidation, whereas PPARGC1B
expression was positively related to fat oxidation and nonoxidative
glucose metabolism. Ling et al. (2004) concluded that insulin stimulates
and aging reduces skeletal muscle expression of PPARGC1A and PPARGC1B,
and suggested that they have different regulatory functions on glucose
and fat oxidation in muscle cells. The authors suggested that this could
provide an explanation by which an environmental trigger (age) modifies
genetic susceptibility to type II diabetes (see 125853).
Lin et al. (2005) found that high-fat feeding stimulated expression of
both Pgc1-beta and Srebp1a/1c (SREBF1; 184756) in mouse liver. Pgc1-beta
coactivated the Srebp transcription factor family and stimulated
lipogenic gene expression. Furthermore, Pgc1-beta was required for
Srebp-mediated lipogenic gene expression. However, unlike Srebp itself,
Pgc1-beta reduced fat accumulation in liver while greatly increasing
circulating triglycerides and cholesterol in very low density
lipoprotein particles. Lin et al. (2005) determined that the stimulation
of lipoprotein transport upon Pgc1-beta expression was likely due to the
simultaneous coactivation of the liver nuclear hormone receptor,
Lxr-alpha (NR1H3; 602423). These data suggested a mechanism through
which dietary saturated fats can stimulate hyperlipidemia and
atherogenesis.
Ishii et al. (2009) found that knockdown of Ppargc1b in primary mouse
osteoclasts impaired their differentiation and mitochondrial biogenesis.
Transferrin receptor-1 (TFRC; 190010) expression was induced in
osteoclasts via iron regulatory protein-2 (IREB2; 147582), and
Tfrc-mediated iron uptake promoted osteoclast differentiation and
bone-resorbing activity, which was associated with the induction of
mitochondrial respiration, production of reactive oxygen species, and
accelerated Ppargc1b transcription. Iron chelation inhibited
osteoclastic bone resorption and protected female mice against bone loss
following estrogen deficiency resulting from ovariectomy. Ishii et al.
(2009) concluded that mitochondrial biogenesis, which is induced by
PPARGC1B and supported by TFRC-mediated iron uptake for utilization by
mitochondrial respiratory proteins, is fundamental to osteoclast
activation and bone metabolism.
Srivastava et al. (2009) tested the potential effect of increased
mitochondrial biogenesis in cells derived from patients harboring
oxidative phosphorylation defects due to either nuclear or mitochondrial
DNA mutations. Adenoviral-mediated expression of PPARGC1A and/or
PPARGC1B improved mitochondrial respiration in fibroblasts harboring a
complex III deficiency (124000) or complex IV deficiency (220110) as
well as in transmitochondrial cybrids harboring a mutation in the MTTL1
gene (590050.0001), resulting in MELAS syndrome (540000). The
respiratory function improvement was found to be associated with
increased levels of mitochondrial components per cell, although this
increase was not homogeneous.
Sahin et al. (2011) used transcriptomic network analyses in mice null
for either Tert (187270) or Terc (602322), which exhibit telomere
dysfunction, to identify common mechanisms operative in hematopoietic
stem cells, heart, and liver. Their studies revealed profound repression
of peroxisome proliferator-activated receptor-gamma (PPARG; 601487),
PCG1-alpha (604517) and PGC1-beta, and the downstream network.
Consistent with PGCs as master regulators of mitochondrial physiology
and metabolism, telomere dysfunction was associated with impaired
mitochondrial biogenesis and function, decreased gluconeogenesis,
cardiomyopathy, and increased reactive oxygen species. In the setting of
telomere dysfunction, enforced Tert or PGC1-alpha expression or germline
deletion of p53 (191170) substantially restored PGC network expression,
mitochondrial respiration, cardiac function, and gluconeogenesis. Sahin
et al. (2011) demonstrated that telomere dysfunction activates p53 which
in turn binds and represses PGC1-alpha and PGC1-beta promoters, thereby
forging a direct link between telomere and mitochondrial biology. Sahin
et al. (2011) proposed that this telomere-p53-PGC axis contributes to
organ and metabolic failure and to diminishing organismal fitness in the
setting of telomere dysfunction.
MAPPING
Lin et al. (2002) reported that the human PPARGC1B gene maps to 5q33.
Kressler et al. (2002) identified the PPARGC1B gene on chromosome 5.
MOLECULAR GENETICS
In a case-control study of 7,790 individuals, Andersen et al. (2005)
found that the pro203 allele of PPARGC1B (608886.0001) was significantly
less frequent among obese participants than normal or overweight
subjects (p = 0.004). Andersen et al. (2005) concluded that variation of
PPARGC1B may contribute to the pathogenesis of obesity, with the
widespread ala203 allele being a risk factor for the development of this
common disorder.
ANIMAL MODEL
Lai et al. (2008) found that survival rates of Pgc1b -/- mice were
reduced compared with wildtype mice, although they appeared normal and
had normal heart function, similar to Pgc1a -/- mice. However, Pgc1b -/-
mice showed reduced ability to adapt to thermal or exercise challenge,
and Pgc1b -/- mice upregulated Pgc1a expression in heart and brown
adipose tissue, suggesting a compensatory response to increase ATP
synthesis during physiologic challenge. In contrast, Pgc1a/Pgc1b
double-knockout mice died shortly after birth with small hearts,
bradycardia, intermittent heart block, and markedly reduced cardiac
output. Cardiac-specific ablation of the Pgc1b gene on a Pgc1a -/-
background phenocopied Pgc1a/Pgc1b double-knockout mice. The hearts of
double-knockout mice exhibited features of a maturational defect,
including reduced growth, late fetal arrest in mitochondria biogenesis,
and persistence of a fetal pattern of gene expression. Brown adipose
tissue of double-knockout mice also exhibited a severe abnormality in
function and mitochondrial density. Lai et al. (2008) concluded that
PGC1A and PGC1B share roles necessary for postnatal metabolic and
functional maturation of the heart and brown adipose tissue.
Ishii et al. (2009) found that Ppargc1b -/- mice displayed enhanced bone
mass due to impaired bone resorption. Ppargc1b -/- osteoclasts appeared
abnormal and their bone-resorbing activity was significantly impaired.
*FIELD* AV
.0001
OBESITY, VARIATION IN
PPARBC1B, ALA203PRO
In a case-control study of 7,790 individuals, Andersen et al. (2005)
found that alleles carrying a 649G-C transversion in exon 5 of the
PPARGC1B gene, resulting in an ala203-to-pro (A203P) substitution, were
significantly less frequent among obese participants than normal or
overweight subjects (p = 0.004). The ala/ala genotype was found in 84%,
85%, and 88% of normal, overweight, and obese subjects, respectively.
Andersen et al. (2005) concluded that variation of PPARGC1B may
contribute to the pathogenesis of obesity, with the widespread ala203
allele being a risk factor for the development of this common disorder.
The authors noted that they used the most abundant human isoform,
PPARGC1B1a, for numbering codons.
*FIELD* RF
1. Andersen, G.; Wegner, L.; Yanagisawa, K.; Rose, C. S.; Glumer,
C.; Drivsholm, T.; Borch-Johnsen, K.; Jorgensen, T.; Hansen, T.; Spiegelman,
B. M.; Pedersen, O.: Evidence of an association between genetic variation
of the coactivator PGC-1-beta and obesity. J. Med. Genet. 42: 402-407,
2005.
2. Hentschke, M.; Susens, U.; Borgmeyer, U.: PGC-1 and PERC, coactivators
of the estrogen receptor-related receptor gamma. Biochem. Biophys.
Res. Commun. 299: 872-879, 2002.
3. Ishii, K.; Fumoto, T.; Iwai, K.; Takeshita, S.; Ito, M.; Shimohata,
N.; Aburatani, H.; Taketani, S.; Lelliott, C. J.; Vidal-Puig, A.;
Ikeda, K.: Coordination of PGC-1-beta and iron uptake in mitochondrial
biogenesis and osteoclast activation. Nature Med. 15: 259-266, 2009.
4. Kamei, Y.; Ohizumi, H.; Fujitani, Y.; Nemoto, T.; Tanaka, T.; Takahashi,
N.; Kawada, T.; Miyoshi, M.; Ezaki, O.; Kakizuka, A.: PPAR-gamma
coactivator 1-beta/ERR ligand 1 is an ERR protein ligand, whose expression
induces a high-energy expenditure and antagonizes obesity. Proc.
Nat. Acad. Sci. 100: 12378-12383, 2003.
5. Kressler, D.; Schreiber, S. N.; Knutti, D.; Kralli, A.: The PGC-1-related
protein PERC is a selective coactivator of estrogen receptor-alpha. J.
Biol. Chem. 277: 13918-13925, 2002.
6. Lai, L.; Leone, T. C.; Zechner, C.; Schaeffer, P. J.; Kelly, S.
M.; Flanagan, D. P.; Medeiros, D. M.; Kovacs, A.; Kelly, D. P.: Transcriptional
coactivators PGC-1-alpha and PGC-1-beta control overlapping programs
required for perinatal maturation of the heart. Genes Dev. 22: 1948-1961,
2008.
7. Lin, J.; Puigserver, P.; Donovan, J.; Tarr, P.; Spiegelman, B.
M.: Peroxisome proliferator-activated receptor gamma coactivator
1-beta (PGC-1-beta), a novel PGC-1-related transcription coactivator
associated with host cell factor. J. Biol. Chem. 277: 1645-1648,
2002.
8. Lin, J.; Yang, R.; Tarr, P. T.; Wu, P.-H.; Handschin, C.; Li, S.;
Yang, W.; Pei, L.; Uldry, M.; Tontonoz, P.; Newgard, C. B.; Spiegelman,
B. M.: Hyperlipidemic effects of dietary saturated fats mediated
through PGC-1-beta coactivation of SREBP. Cell 120: 261-273, 2005.
9. Ling, C.; Poulsen, P.; Carlsson, E.; Ridderstrale, M.; Almgren,
P.; Wojtaszewski, J.; Beck-Nielsen, H.; Groop, L.; Vaag, A.: Multiple
environmental and genetic factors influence skeletal muscle PGC-1-alpha
and PGC-1-beta gene expression in twins. J. Clin. Invest. 114: 1518-1526,
2004.
10. Sahin, E.; Colla, S.; Liesa, M.; Moslehi, J.; Muller, F. L.; Guo,
M.; Cooper, M.; Kotton, D.; Fabian, A. J.; Walkey, C.; Maser, R. S.;
Tonon, G.; and 18 others: Telomere dysfunction induces metabolic
and mitochondrial compromise. Nature 470: 359-365, 2011. Note: Erratum:
Nature 475: 254 only, 2011.
11. Srivastava, S.; Diaz, F.; Iommarini, L.; Aure, K.; Lombes, A.;
Moraes, C. T.: PGC-1-alpha/beta induced expression partially compensates
for respiratory chain defects in cells from patients with mitochondrial
disorders. Hum. Molec. Genet. 18: 1805-1812, 2009.
*FIELD* CN
Ada Hamosh - updated: 7/5/2011
George E. Tiller - updated: 2/22/2010
Patricia A. Hartz - updated: 6/8/2009
Patricia A. Hartz - updated: 9/2/2008
Patricia A. Hartz - updated: 10/19/2005
Marla J. F. O'Neill - updated: 6/20/2005
Stylianos E. Antonarakis - updated: 2/16/2005
Marla J. F. O'Neill - updated: 2/1/2005
*FIELD* CD
Laura L. Baxter: 8/30/2004
*FIELD* ED
alopez: 08/25/2011
alopez: 7/5/2011
wwang: 2/24/2010
terry: 2/22/2010
wwang: 6/11/2009
terry: 6/8/2009
wwang: 9/3/2008
terry: 9/2/2008
terry: 2/3/2006
mgross: 11/1/2005
terry: 10/19/2005
wwang: 6/22/2005
wwang: 6/20/2005
mgross: 2/16/2005
carol: 2/1/2005
alopez: 8/30/2004
*RECORD*
*FIELD* NO
608886
*FIELD* TI
*608886 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, BETA;
PPARGC1B
read more;;PPAR-GAMMA COACTIVATOR 1-BETA; PGC1B;;
PGC1-BETA;;
PGC1-RELATED ESTROGEN RECEPTOR COACTIVATOR; PERC;;
ESTROGEN RECEPTOR-RELATED RECEPTOR LIGAND 1; ERRL1
*FIELD* TX
CLONING
By searching genomic databases with sequence of mouse Pcg1 (PPARGC1A;
604517) as query, Lin et al. (2002) identified a homologous mouse gene,
termed Ppargc1b. Ppargc1b encodes a predicted 1,014-amino acid protein,
and human and mouse PPARGC1B share 70% amino acid sequence identity.
Ppargc1b contains 3 N-terminal LXXLL motifs, 2 glutamic/aspartic
acid-rich acidic domains, a binding site for host cell factor (HCF1;
300019), and a C-terminal RNA recognition motif. Northern blot analysis
showed abundant expression of 9- and 5-kb mouse Ppargc1b transcripts in
brown adipose tissue and heart, and moderate expression in skeletal
muscle, liver, and white adipose tissue.
Kressler et al. (2002) used RT-PCR to amplify full-length human
PPARGC1B, which they referred to as PERC (PGC1-related estrogen receptor
coactivator), from HeLa cells. PPARGC1B encodes a 1,023-amino acid
protein with the same structural features as Ppargc1b, reported by Lin
et al. (2002), and a shorter isoform lacking 39 amino acids (residues
156-194). Immunofluorescence analysis showed that PPARGC1B localizes to
the nucleus. RT-PCR analysis of mouse Ppargc1b showed abundant
expression of the long isoform in heart and skeletal muscle,
intermediate levels in brain, kidney, liver, and adrenal gland, and low
levels in ovary, intestine, and white adipose tissue.
GENE FUNCTION
Lin et al. (2002) showed that murine Ppargc1b shows no change of
expression in brown adipose cells in response to cold exposure, and that
Ppargc1b and Pgc1 have inverse expression levels during brown fat cell
differentiation. However, Ppargc1b expression is increased in liver
during fasting, similar to Pgc1. Immunoprecipitation and reporter
construct activation showed that Ppargc1b interacts with and enhances
the activity of hepatic nuclear factor-4 (600281), peroxisome
proliferator-activated receptor-alpha (170998), and glucocorticoid
receptor (138040). Immunoprecipitation showed HCF1 binds to Ppargc1b and
can increase Ppargc1b transcriptional activity. Ppargc1b is also a
potent regulator of the transcriptional activity of NRF1 (600879), a
central transcription factor in the control of mitochondrial biogenesis.
By transfection of COS-7 cells followed by reporter construct
activation, Kressler et al. (2002) showed that PPARGC1B coactivates
estrogen receptor-alpha (ESR1; 133430). Yeast 2-hybrid analysis showed
ligand-dependent binding of the 2 LXXLL motifs of PPARGC1B to the
ligand-binding domain of ESR1. The PPARGC1B LXXLL motifs and the ESR1
ligand-binding domain are necessary for ESR1 coactivation. An N-terminal
transcriptional activation domain in PPARGC1B is also necessary for ESR1
coactivation. PPARGC1B differed from PPARGC1A in its enhancement of ESR1
activation in various promoter constructs, and PPARGC1B enhanced
ESR1-mediated response to the partial agonist tamoxifen while PPARGC1A
repressed it.
Using cotransfection assays in mammalian cells, Hentschke et al. (2002)
showed that mouse Ppargc1b coactivates estrogen-related receptor-gamma
(ESRRG; 602969). GST pull-down assays showed that Ppargc1b binds ESRRG
in vitro.
Kamei et al. (2003) showed that PGC1B functioned as a ligand for orphan
estrogen receptor-related receptors (ERRs) in vitro. They found that
transgenic mice overexpressing Pgc1b exhibited increased expression of
medium-chain acyl-CoA dehydrogenase (ACADM; 607008), an ERR target and a
pivotal enzyme in mitochondrial beta oxidation in skeletal muscle. As a
result, transgenic mice were hyperphagic, showed elevated energy
expenditure, and were resistant to obesity induced by a high-fat diet or
by genetic abnormality. Kamei et al. (2003) concluded that PGC1B
functions as an ERR ligand and contributes to the control of energy
balance in vivo.
To examine the influence of genetic and environmental factors on the
expression of PPARGC1A and PPARGC1B in human skeletal muscle, Ling et
al. (2004) studied mRNA expression of these transcriptional coactivators
in muscle biopsies from young and elderly monozygotic and dizygotic
twins before and after a hyperinsulinemic euglycemic clamp and found
that insulin increased and aging reduced PPARGC1A and PPARGC1B mRNA
levels. Expression of PPARGC1A in muscle was positively related to
insulin-stimulated glucose uptake and oxidation, whereas PPARGC1B
expression was positively related to fat oxidation and nonoxidative
glucose metabolism. Ling et al. (2004) concluded that insulin stimulates
and aging reduces skeletal muscle expression of PPARGC1A and PPARGC1B,
and suggested that they have different regulatory functions on glucose
and fat oxidation in muscle cells. The authors suggested that this could
provide an explanation by which an environmental trigger (age) modifies
genetic susceptibility to type II diabetes (see 125853).
Lin et al. (2005) found that high-fat feeding stimulated expression of
both Pgc1-beta and Srebp1a/1c (SREBF1; 184756) in mouse liver. Pgc1-beta
coactivated the Srebp transcription factor family and stimulated
lipogenic gene expression. Furthermore, Pgc1-beta was required for
Srebp-mediated lipogenic gene expression. However, unlike Srebp itself,
Pgc1-beta reduced fat accumulation in liver while greatly increasing
circulating triglycerides and cholesterol in very low density
lipoprotein particles. Lin et al. (2005) determined that the stimulation
of lipoprotein transport upon Pgc1-beta expression was likely due to the
simultaneous coactivation of the liver nuclear hormone receptor,
Lxr-alpha (NR1H3; 602423). These data suggested a mechanism through
which dietary saturated fats can stimulate hyperlipidemia and
atherogenesis.
Ishii et al. (2009) found that knockdown of Ppargc1b in primary mouse
osteoclasts impaired their differentiation and mitochondrial biogenesis.
Transferrin receptor-1 (TFRC; 190010) expression was induced in
osteoclasts via iron regulatory protein-2 (IREB2; 147582), and
Tfrc-mediated iron uptake promoted osteoclast differentiation and
bone-resorbing activity, which was associated with the induction of
mitochondrial respiration, production of reactive oxygen species, and
accelerated Ppargc1b transcription. Iron chelation inhibited
osteoclastic bone resorption and protected female mice against bone loss
following estrogen deficiency resulting from ovariectomy. Ishii et al.
(2009) concluded that mitochondrial biogenesis, which is induced by
PPARGC1B and supported by TFRC-mediated iron uptake for utilization by
mitochondrial respiratory proteins, is fundamental to osteoclast
activation and bone metabolism.
Srivastava et al. (2009) tested the potential effect of increased
mitochondrial biogenesis in cells derived from patients harboring
oxidative phosphorylation defects due to either nuclear or mitochondrial
DNA mutations. Adenoviral-mediated expression of PPARGC1A and/or
PPARGC1B improved mitochondrial respiration in fibroblasts harboring a
complex III deficiency (124000) or complex IV deficiency (220110) as
well as in transmitochondrial cybrids harboring a mutation in the MTTL1
gene (590050.0001), resulting in MELAS syndrome (540000). The
respiratory function improvement was found to be associated with
increased levels of mitochondrial components per cell, although this
increase was not homogeneous.
Sahin et al. (2011) used transcriptomic network analyses in mice null
for either Tert (187270) or Terc (602322), which exhibit telomere
dysfunction, to identify common mechanisms operative in hematopoietic
stem cells, heart, and liver. Their studies revealed profound repression
of peroxisome proliferator-activated receptor-gamma (PPARG; 601487),
PCG1-alpha (604517) and PGC1-beta, and the downstream network.
Consistent with PGCs as master regulators of mitochondrial physiology
and metabolism, telomere dysfunction was associated with impaired
mitochondrial biogenesis and function, decreased gluconeogenesis,
cardiomyopathy, and increased reactive oxygen species. In the setting of
telomere dysfunction, enforced Tert or PGC1-alpha expression or germline
deletion of p53 (191170) substantially restored PGC network expression,
mitochondrial respiration, cardiac function, and gluconeogenesis. Sahin
et al. (2011) demonstrated that telomere dysfunction activates p53 which
in turn binds and represses PGC1-alpha and PGC1-beta promoters, thereby
forging a direct link between telomere and mitochondrial biology. Sahin
et al. (2011) proposed that this telomere-p53-PGC axis contributes to
organ and metabolic failure and to diminishing organismal fitness in the
setting of telomere dysfunction.
MAPPING
Lin et al. (2002) reported that the human PPARGC1B gene maps to 5q33.
Kressler et al. (2002) identified the PPARGC1B gene on chromosome 5.
MOLECULAR GENETICS
In a case-control study of 7,790 individuals, Andersen et al. (2005)
found that the pro203 allele of PPARGC1B (608886.0001) was significantly
less frequent among obese participants than normal or overweight
subjects (p = 0.004). Andersen et al. (2005) concluded that variation of
PPARGC1B may contribute to the pathogenesis of obesity, with the
widespread ala203 allele being a risk factor for the development of this
common disorder.
ANIMAL MODEL
Lai et al. (2008) found that survival rates of Pgc1b -/- mice were
reduced compared with wildtype mice, although they appeared normal and
had normal heart function, similar to Pgc1a -/- mice. However, Pgc1b -/-
mice showed reduced ability to adapt to thermal or exercise challenge,
and Pgc1b -/- mice upregulated Pgc1a expression in heart and brown
adipose tissue, suggesting a compensatory response to increase ATP
synthesis during physiologic challenge. In contrast, Pgc1a/Pgc1b
double-knockout mice died shortly after birth with small hearts,
bradycardia, intermittent heart block, and markedly reduced cardiac
output. Cardiac-specific ablation of the Pgc1b gene on a Pgc1a -/-
background phenocopied Pgc1a/Pgc1b double-knockout mice. The hearts of
double-knockout mice exhibited features of a maturational defect,
including reduced growth, late fetal arrest in mitochondria biogenesis,
and persistence of a fetal pattern of gene expression. Brown adipose
tissue of double-knockout mice also exhibited a severe abnormality in
function and mitochondrial density. Lai et al. (2008) concluded that
PGC1A and PGC1B share roles necessary for postnatal metabolic and
functional maturation of the heart and brown adipose tissue.
Ishii et al. (2009) found that Ppargc1b -/- mice displayed enhanced bone
mass due to impaired bone resorption. Ppargc1b -/- osteoclasts appeared
abnormal and their bone-resorbing activity was significantly impaired.
*FIELD* AV
.0001
OBESITY, VARIATION IN
PPARBC1B, ALA203PRO
In a case-control study of 7,790 individuals, Andersen et al. (2005)
found that alleles carrying a 649G-C transversion in exon 5 of the
PPARGC1B gene, resulting in an ala203-to-pro (A203P) substitution, were
significantly less frequent among obese participants than normal or
overweight subjects (p = 0.004). The ala/ala genotype was found in 84%,
85%, and 88% of normal, overweight, and obese subjects, respectively.
Andersen et al. (2005) concluded that variation of PPARGC1B may
contribute to the pathogenesis of obesity, with the widespread ala203
allele being a risk factor for the development of this common disorder.
The authors noted that they used the most abundant human isoform,
PPARGC1B1a, for numbering codons.
*FIELD* RF
1. Andersen, G.; Wegner, L.; Yanagisawa, K.; Rose, C. S.; Glumer,
C.; Drivsholm, T.; Borch-Johnsen, K.; Jorgensen, T.; Hansen, T.; Spiegelman,
B. M.; Pedersen, O.: Evidence of an association between genetic variation
of the coactivator PGC-1-beta and obesity. J. Med. Genet. 42: 402-407,
2005.
2. Hentschke, M.; Susens, U.; Borgmeyer, U.: PGC-1 and PERC, coactivators
of the estrogen receptor-related receptor gamma. Biochem. Biophys.
Res. Commun. 299: 872-879, 2002.
3. Ishii, K.; Fumoto, T.; Iwai, K.; Takeshita, S.; Ito, M.; Shimohata,
N.; Aburatani, H.; Taketani, S.; Lelliott, C. J.; Vidal-Puig, A.;
Ikeda, K.: Coordination of PGC-1-beta and iron uptake in mitochondrial
biogenesis and osteoclast activation. Nature Med. 15: 259-266, 2009.
4. Kamei, Y.; Ohizumi, H.; Fujitani, Y.; Nemoto, T.; Tanaka, T.; Takahashi,
N.; Kawada, T.; Miyoshi, M.; Ezaki, O.; Kakizuka, A.: PPAR-gamma
coactivator 1-beta/ERR ligand 1 is an ERR protein ligand, whose expression
induces a high-energy expenditure and antagonizes obesity. Proc.
Nat. Acad. Sci. 100: 12378-12383, 2003.
5. Kressler, D.; Schreiber, S. N.; Knutti, D.; Kralli, A.: The PGC-1-related
protein PERC is a selective coactivator of estrogen receptor-alpha. J.
Biol. Chem. 277: 13918-13925, 2002.
6. Lai, L.; Leone, T. C.; Zechner, C.; Schaeffer, P. J.; Kelly, S.
M.; Flanagan, D. P.; Medeiros, D. M.; Kovacs, A.; Kelly, D. P.: Transcriptional
coactivators PGC-1-alpha and PGC-1-beta control overlapping programs
required for perinatal maturation of the heart. Genes Dev. 22: 1948-1961,
2008.
7. Lin, J.; Puigserver, P.; Donovan, J.; Tarr, P.; Spiegelman, B.
M.: Peroxisome proliferator-activated receptor gamma coactivator
1-beta (PGC-1-beta), a novel PGC-1-related transcription coactivator
associated with host cell factor. J. Biol. Chem. 277: 1645-1648,
2002.
8. Lin, J.; Yang, R.; Tarr, P. T.; Wu, P.-H.; Handschin, C.; Li, S.;
Yang, W.; Pei, L.; Uldry, M.; Tontonoz, P.; Newgard, C. B.; Spiegelman,
B. M.: Hyperlipidemic effects of dietary saturated fats mediated
through PGC-1-beta coactivation of SREBP. Cell 120: 261-273, 2005.
9. Ling, C.; Poulsen, P.; Carlsson, E.; Ridderstrale, M.; Almgren,
P.; Wojtaszewski, J.; Beck-Nielsen, H.; Groop, L.; Vaag, A.: Multiple
environmental and genetic factors influence skeletal muscle PGC-1-alpha
and PGC-1-beta gene expression in twins. J. Clin. Invest. 114: 1518-1526,
2004.
10. Sahin, E.; Colla, S.; Liesa, M.; Moslehi, J.; Muller, F. L.; Guo,
M.; Cooper, M.; Kotton, D.; Fabian, A. J.; Walkey, C.; Maser, R. S.;
Tonon, G.; and 18 others: Telomere dysfunction induces metabolic
and mitochondrial compromise. Nature 470: 359-365, 2011. Note: Erratum:
Nature 475: 254 only, 2011.
11. Srivastava, S.; Diaz, F.; Iommarini, L.; Aure, K.; Lombes, A.;
Moraes, C. T.: PGC-1-alpha/beta induced expression partially compensates
for respiratory chain defects in cells from patients with mitochondrial
disorders. Hum. Molec. Genet. 18: 1805-1812, 2009.
*FIELD* CN
Ada Hamosh - updated: 7/5/2011
George E. Tiller - updated: 2/22/2010
Patricia A. Hartz - updated: 6/8/2009
Patricia A. Hartz - updated: 9/2/2008
Patricia A. Hartz - updated: 10/19/2005
Marla J. F. O'Neill - updated: 6/20/2005
Stylianos E. Antonarakis - updated: 2/16/2005
Marla J. F. O'Neill - updated: 2/1/2005
*FIELD* CD
Laura L. Baxter: 8/30/2004
*FIELD* ED
alopez: 08/25/2011
alopez: 7/5/2011
wwang: 2/24/2010
terry: 2/22/2010
wwang: 6/11/2009
terry: 6/8/2009
wwang: 9/3/2008
terry: 9/2/2008
terry: 2/3/2006
mgross: 11/1/2005
terry: 10/19/2005
wwang: 6/22/2005
wwang: 6/20/2005
mgross: 2/16/2005
carol: 2/1/2005
alopez: 8/30/2004