RBCC Red Blood Cell Collection

BCL10 (CIPER, CLAP) [Confidence: low (only semi-automatic identification from reviews)]
B-cell lymphoma/leukemia 10 (B-cell CLL/lymphoma 10; Bcl-10; CARD-containing molecule enhancing NF-kappa-B; CARD-like apoptotic protein; hCLAP; CED-3/ICH-1 prodomain homologous E10-like regulator; CIPER; Cellular homolog of vCARMEN; cCARMEN; Cellular-E10; c-E10; Mammalian CARD-containing adapter molecule E10; mE10)

UniProt O95999
ID BCL10_HUMAN Reviewed; 233 AA.
AC O95999; Q5VUF1;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1999, sequence version 1.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=B-cell lymphoma/leukemia 10;
DE AltName: Full=B-cell CLL/lymphoma 10;
DE Short=Bcl-10;
DE AltName: Full=CARD-containing molecule enhancing NF-kappa-B;
DE AltName: Full=CARD-like apoptotic protein;
DE Short=hCLAP;
DE AltName: Full=CED-3/ICH-1 prodomain homologous E10-like regulator;
DE Short=CIPER;
DE AltName: Full=Cellular homolog of vCARMEN;
DE Short=cCARMEN;
DE AltName: Full=Cellular-E10;
DE Short=c-E10;
DE AltName: Full=Mammalian CARD-containing adapter molecule E10;
DE Short=mE10;
GN Name=BCL10; Synonyms=CIPER, CLAP;
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], VARIANT FOLLICULAR LYMPHOMA GLU-210 DEL,
RP VARIANT MESOTHELIOMA ILE-52, AND VARIANTS GERM CELL TUMOR GLY-58 AND
RP PHE-218.
RC TISSUE=Lymphoma;
RX PubMed=9989495; DOI=10.1016/S0092-8674(00)80957-5;
RA Willis T.G., Jadayel D.M., Du M.-Q., Peng H., Perry A.R.,
RA Abdul-Rauf M., Price H., Karran L., Majekodunmi O., Wlodarska I.,
RA Pan L., Crook T., Hamoudi R., Isaacson P., Dyer M.J.S.;
RT "Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and
RT mutated in multiple tumor types.";
RL Cell 96:35-45(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND MUTAGENESIS OF LEU-41 AND GLY-78.
RX PubMed=10187770; DOI=10.1074/jbc.274.15.9955;
RA Koseki T., Inohara N., Chen S., Carrio R., Merino J., Hottiger M.O.,
RA Nabel G.J., Nunez G.;
RT "CIPER, a novel NF kappaB-activating protein containing a caspase
RT recruitment domain with homology to Herpesvirus-2 protein E10.";
RL J. Biol. Chem. 274:9955-9961(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10187771; DOI=10.1074/jbc.274.15.9962;
RA Thome M., Martinon F., Hofmann K., Rubio V., Steiner V., Schneider P.,
RA Mattmann C., Tschopp J.;
RT "Equine herpesvirus-2 E10 gene product, but not its cellular
RT homologue, activates NF-kappaB transcription factor and c-Jun N-
RT terminal kinase.";
RL J. Biol. Chem. 274:9962-9968(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND MUTAGENESIS OF LEU-28; LEU-41; ILE-46;
RP LEU-47; GLU-53 AND ILE-55.
RX PubMed=10187815; DOI=10.1074/jbc.274.15.10287;
RA Yan M., Lee J., Schilbach S., Goddard A., Dixit V.M.;
RT "mE10, a novel caspase recruitment domain-containing proapoptotic
RT molecule.";
RL J. Biol. Chem. 274:10287-10292(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10364242; DOI=10.1074/jbc.274.25.17946;
RA Srinivasula S.M., Ahmad M., Lin J.-H., Poyet J.-L.,
RA Fernandes-Alnemri T., Tsichlis P.N., Alnemri E.S.;
RT "CLAP, a novel caspase recruitment domain-containing protein in the
RT tumor necrosis factor receptor pathway, regulates NF-kappaB activation
RT and apoptosis.";
RL J. Biol. Chem. 274:17946-17954(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Spleen;
RX PubMed=10400625; DOI=10.1074/jbc.274.29.20127;
RA Costanzo A., Guiet C., Vito P.;
RT "c-E10 is a caspase-recruiting domain-containing protein that
RT interacts with components of death receptors signaling pathway and
RT activates nuclear factor-kappaB.";
RL J. Biol. Chem. 274:20127-20132(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANTS MALT LYMPHOMA
RP SER-5; GLU-16; GLU-31; ARG-57; LYS-64; GLU-101; PRO-134; ALA-168;
RP SER-174; GLU-213 AND ILE-230.
RX PubMed=10319863; DOI=10.1038/8767;
RA Zhang Q., Siebert R., Yan M., Hinzmann B., Cui X., Xue L.,
RA Rakestraw K.M., Naeve C.W., Beckmann G., Weisenburger D.D.,
RA Sanger W.G., Nowotny H., Vesely M., Callet-Bauchu E., Salles G.,
RA Dixit V.M., Rosenthal A., Schlegelberger B., Morris S.W.;
RT "Inactivating mutations and overexpression of BCL10, a caspase
RT recruitment domain-containing gene, in MALT lymphoma with
RT t(1;14)(p22;q32).";
RL Nat. Genet. 22:63-68(1999).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
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 [12]
RP PHOSPHORYLATION.
RX PubMed=11466612; DOI=10.1038/sj.onc.1204576;
RA Yui D., Yoneda T., Oono K., Katayama T., Imaizumi K., Tohyama M.;
RT "Interchangeable binding of Bcl10 to TRAF2 and cIAPs regulates
RT apoptosis signaling.";
RL Oncogene 20:4317-4323(2001).
RN [13]
RP IDENTIFICATION IN A MEMBRANE RAFT COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=17287217; DOI=10.1074/jbc.M609157200;
RA Ohnuma K., Uchiyama M., Yamochi T., Nishibashi K., Hosono O.,
RA Takahashi N., Kina S., Tanaka H., Lin X., Dang N.H., Morimoto C.;
RT "Caveolin-1 triggers T-cell activation via CD26 in association with
RT CARMA1.";
RL J. Biol. Chem. 282:10117-10131(2007).
RN [14]
RP PHOSPHORYLATION BY IKBKB/IKKB, AND MUTAGENESIS OF 81-THR--SER-85.
RX PubMed=17213322; DOI=10.1073/pnas.0606982104;
RA Lobry C., Lopez T., Israel A., Weil R.;
RT "Negative feedback loop in T cell activation through IkappaB kinase-
RT induced phosphorylation and degradation of Bcl10.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:908-913(2007).
RN [15]
RP FUNCTION, AND MUTAGENESIS OF ARG-228.
RX PubMed=18264101; DOI=10.1038/ni1568;
RA Rebeaud F., Hailfinger S., Posevitz-Fejfar A., Tapernoux M., Moser R.,
RA Rueda D., Gaide O., Guzzardi M., Iancu E.M., Rufer N., Fasel N.,
RA Thome M.;
RT "The proteolytic activity of the paracaspase MALT1 is key in T cell
RT activation.";
RL Nat. Immunol. 9:272-281(2008).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP VARIANTS MESOTHELIOMA SER-5; GLN-45; GLN-58; SER-93; VAL-153; GLU-213
RP AND PHE-218.
RX PubMed=10380921; DOI=10.1016/S0092-8674(02)09765-9;
RA Apostolou S., de Rienzo A., Murthy S.S., Jhanwar S.C., Testa J.R.;
RT "Absence of BCL10 mutations in human malignant mesothelioma.";
RL Cell 97:684-686(1999).
CC -!- FUNCTION: Promotes apoptosis, pro-caspase-9 maturation and
CC activation of NF-kappa-B via NIK and IKK. May be an adapter
CC protein between upstream TNFR1-TRADD-RIP complex and the
CC downstream NIK-IKK-IKAP complex. Is a substrate for MALT1.
CC -!- SUBUNIT: Found in a membrane raft complex, at least composed of
CC BCL10, CARD11, DPP4 and IKBKB. Self-associates by CARD-CARD
CC interaction and forms a tight complex with MALT1. Interacts with
CC other CARD-proteins such as CARD9, CARD10, CARD11 and CARD14.
CC Binds caspase-9 with its C-terminal domain. Interacts with TRAF2
CC and BIRC2/c-IAP2. Interacts with PELI2 and SOCS3; these
CC interactions may be mutually exclusive (By similarity).
CC -!- INTERACTION:
CC P31749:AKT1; NbExp=4; IntAct=EBI-958922, EBI-296087;
CC P20749:BCL3; NbExp=3; IntAct=EBI-958922, EBI-958997;
CC Q9BXL7:CARD11; NbExp=4; IntAct=EBI-958922, EBI-7006141;
CC Q9UDY8:MALT1; NbExp=12; IntAct=EBI-958922, EBI-1047372;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region. Membrane
CC raft. Note=Appears to have a perinuclear, compact and filamentous
CC pattern of expression. Also found in the nucleus of several types
CC of tumor cells. Colocalized with DPP4 in membrane rafts.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Phosphorylated. Phosphorylation results in dissociation from
CC TRAF2 and binding to BIRC2/c-IAP2. Phosphorylated by IKBKB/IKKB.
CC -!- DISEASE: Note=A chromosomal aberration involving BCL10 is
CC recurrent in low-grade mucosa-associated lymphoid tissue (MALT
CC lymphoma). Translocation t(1;14)(p22;q32). Although the BCL10/IgH
CC translocation leaves the coding region of BCL10 intact, frequent
CC BCL10 mutations could be attributed to the Ig somatic
CC hypermutation mechanism resulting in nucleotide transitions.
CC -!- DISEASE: Note=Defects in BCL10 are involved in various types of
CC cancer.
CC -!- DISEASE: Mesothelioma, malignant (MESOM) [MIM:156240]: An
CC aggressive neoplasm of the serosal lining of the chest. It appears
CC as broad sheets of cells, with some regions containing spindle-
CC shaped, sarcoma-like cells and other regions showing adenomatous
CC patterns. Pleural mesotheliomas have been linked to exposure to
CC asbestos. Note=The gene represented in this entry may be involved
CC in disease pathogenesis.
CC -!- SIMILARITY: Contains 1 CARD domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/BCL10ID222ch1p22.html";
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DR EMBL; AJ006288; CAA06955.1; -; mRNA.
DR EMBL; AF057700; AAD15800.1; -; mRNA.
DR EMBL; AF100338; AAD16428.1; -; mRNA.
DR EMBL; AF127386; AAD32597.1; -; mRNA.
DR EMBL; AF134395; AAD39147.1; -; mRNA.
DR EMBL; AF105066; AAF06894.1; -; mRNA.
DR EMBL; AF082283; AAC99767.1; -; mRNA.
DR EMBL; AF097732; AAD24918.1; -; Genomic_DNA.
DR EMBL; AK291346; BAF84035.1; -; mRNA.
DR EMBL; AL590113; CAH71557.1; -; Genomic_DNA.
DR EMBL; CH471097; EAW73208.1; -; Genomic_DNA.
DR EMBL; BC053617; AAH53617.1; -; mRNA.
DR RefSeq; NP_003912.1; NM_003921.4.
DR UniGene; Hs.193516; -.
DR PDB; 2MB9; NMR; -; A=1-115.
DR PDBsum; 2MB9; -.
DR ProteinModelPortal; O95999; -.
DR SMR; O95999; 15-89.
DR DIP; DIP-29740N; -.
DR IntAct; O95999; 18.
DR MINT; MINT-89139; -.
DR STRING; 9606.ENSP00000271015; -.
DR PhosphoSite; O95999; -.
DR PaxDb; O95999; -.
DR PRIDE; O95999; -.
DR DNASU; 8915; -.
DR Ensembl; ENST00000370580; ENSP00000359612; ENSG00000142867.
DR GeneID; 8915; -.
DR KEGG; hsa:8915; -.
DR UCSC; uc021opd.1; human.
DR CTD; 8915; -.
DR GeneCards; GC01M085731; -.
DR HGNC; HGNC:989; BCL10.
DR HPA; CAB001944; -.
DR HPA; HPA017925; -.
DR MIM; 156240; phenotype.
DR MIM; 603517; gene.
DR neXtProt; NX_O95999; -.
DR PharmGKB; PA25299; -.
DR eggNOG; NOG44778; -.
DR HOGENOM; HOG000008671; -.
DR HOVERGEN; HBG050680; -.
DR InParanoid; O95999; -.
DR KO; K07368; -.
DR OMA; GGTCGNS; -.
DR OrthoDB; EOG79W97M; -.
DR PhylomeDB; O95999; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; O95999; -.
DR ChiTaRS; BCL10; human.
DR GeneWiki; BCL10; -.
DR GenomeRNAi; 8915; -.
DR NextBio; 33536; -.
DR PRO; PR:O95999; -.
DR Bgee; O95999; -.
DR CleanEx; HS_BCL10; -.
DR Genevestigator; O95999; -.
DR GO; GO:0032449; C:CBM complex; NAS:UniProtKB.
DR GO; GO:0005881; C:cytoplasmic microtubule; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0051059; F:NF-kappaB binding; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; TAS:UniProtKB.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; IDA:UniProtKB.
DR GO; GO:0006968; P:cellular defense response; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; IEA:Ensembl.
DR GO; GO:0016064; P:immunoglobulin mediated immune response; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IEP:UniProtKB.
DR GO; GO:0042226; P:interleukin-6 biosynthetic process; NAS:UniProtKB.
DR GO; GO:0042109; P:lymphotoxin A biosynthetic process; NAS:UniProtKB.
DR GO; GO:0002906; P:negative regulation of mature B cell apoptotic process; IDA:UniProtKB.
DR GO; GO:0001843; P:neural tube closure; ISS:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0045416; P:positive regulation of interleukin-8 biosynthetic process; IMP:UniProtKB.
DR GO; GO:0032765; P:positive regulation of mast cell cytokine production; NAS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:UniProtKB.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0050870; P:positive regulation of T cell activation; IEA:Ensembl.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB.
DR GO; GO:0050856; P:regulation of T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0009620; P:response to fungus; IEA:Ensembl.
DR GO; GO:0002237; P:response to molecule of bacterial origin; IEP:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0002224; P:toll-like receptor signaling pathway; IC:UniProtKB.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR011029; DEATH-like_dom.
DR Pfam; PF00619; CARD; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50209; CARD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Apoptosis; Chromosomal rearrangement;
KW Complete proteome; Cytoplasm; Disease mutation; Membrane;
KW Phosphoprotein; Reference proteome; Tumor suppressor.
FT CHAIN 1 233 B-cell lymphoma/leukemia 10.
FT /FTId=PRO_0000144074.
FT DOMAIN 13 101 CARD.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 138 138 Phosphoserine.
FT VARIANT 5 5 A -> S (in MALT lymphoma and
FT mesothelioma; dbSNP:rs12037217).
FT /FTId=VAR_013208.
FT VARIANT 16 16 V -> E (in MALT lymphoma).
FT /FTId=VAR_013209.
FT VARIANT 31 31 K -> E (in MALT lymphoma).
FT /FTId=VAR_013210.
FT VARIANT 45 45 K -> Q (in mesothelioma).
FT /FTId=VAR_013211.
FT VARIANT 52 52 T -> I (in mesothelioma).
FT /FTId=VAR_013212.
FT VARIANT 57 57 C -> R (in MALT lymphoma).
FT /FTId=VAR_013213.
FT VARIANT 58 58 R -> G (in germ cell tumor).
FT /FTId=VAR_013214.
FT VARIANT 58 58 R -> Q (in mesothelioma).
FT /FTId=VAR_013215.
FT VARIANT 64 64 R -> K (in MALT lymphoma).
FT /FTId=VAR_013216.
FT VARIANT 93 93 N -> S (in mesothelioma).
FT /FTId=VAR_013217.
FT VARIANT 101 101 D -> E (in MALT lymphoma).
FT /FTId=VAR_013218.
FT VARIANT 134 134 S -> P (in MALT lymphoma).
FT /FTId=VAR_013219.
FT VARIANT 153 153 M -> V (in mesothelioma).
FT /FTId=VAR_013220.
FT VARIANT 168 168 T -> A (in MALT lymphoma).
FT /FTId=VAR_013221.
FT VARIANT 174 174 L -> S (in MALT lymphoma).
FT /FTId=VAR_013222.
FT VARIANT 210 210 Missing (in follicular lymphoma).
FT /FTId=VAR_013223.
FT VARIANT 213 213 G -> E (in MALT lymphoma and
FT mesothelioma; dbSNP:rs3768235).
FT /FTId=VAR_013224.
FT VARIANT 218 218 S -> F (in germ cell tumor, mesothelioma
FT and other cancer cell lines).
FT /FTId=VAR_013225.
FT VARIANT 230 230 V -> I (in MALT lymphoma).
FT /FTId=VAR_013226.
FT MUTAGEN 28 28 L->A: Abolishes cell death-inducing
FT capability.
FT MUTAGEN 41 41 L->A: Abolishes cell death-inducing
FT capability.
FT MUTAGEN 41 41 L->Q: Abolishes NF-kappa-B activation and
FT homo/hetero-dimerization.
FT MUTAGEN 46 46 I->A: Abolishes cell death-inducing
FT capability.
FT MUTAGEN 47 47 L->A: Abolishes cell death-inducing
FT capability.
FT MUTAGEN 53 53 E->A: Abolishes cell death-inducing
FT capability.
FT MUTAGEN 55 55 I->A: Abolishes cell death-inducing
FT capability.
FT MUTAGEN 78 78 G->R: Abolishes NF-kappa-B activation.
FT MUTAGEN 81 85 TLVES->ALVEA: Complete loss of
FT IKBKB/IKKB-mediated phosphorylation.
FT MUTAGEN 228 228 R->G: Abolishes MALT1-mediated cleavage.
FT MUTAGEN 231 231 S->A: Promotes NF-kappa-B activation.
SQ SEQUENCE 233 AA; 26252 MW; F87C97F2B784BA4B CRC64;
MEPTAPSLTE EDLTEVKKDA LENLRVYLCE KIIAERHFDH LRAKKILSRE DTEEISCRTS
SRKRAGKLLD YLQENPKGLD TLVESIRREK TQNFLIQKIT DEVLKLRNIK LEHLKGLKCS
SCEPFPDGAT NNLSRSNSDE SNFSEKLRAS TVMYHPEGES STTPFFSTNS SLNLPVLEVG
RTENTIFSST TLPRPGDPGA PPLPPDLQLE EEGTCANSSE MFLPLRSRTV SRQ
//

MIM 156240
*RECORD*
*FIELD* NO
156240
*FIELD* TI
#156240 MESOTHELIOMA, MALIGNANT; MESOM
*FIELD* TX
A number sign (#) is used with this entry because somatic mutations in
read moreseveral genes have been identified in malignant mesothelioma. These
genes include WT1 (607102) on chromosome 11p13, BCL10 (603517) on
chromosome 1p22, CDKN2A (600160) on chromosome 9p21, NF2 (607379) on
chromosome 22q12, and BAP1 (603089) on chromosome 3p21.

DESCRIPTION

Malignant mesothelioma is an aggressive neoplasm of the serosal lining
of the chest etiologically linked to asbestos. It is diagnosed in
approximately 2,000 to 3,000 individuals annually in the United States,
most of whom die within 2 years of diagnosis (summary by Bott et al.,
2011).

See also 614327 for a tumor predisposition syndrome that may contribute
to the development of malignant mesothelioma upon asbestos exposure and
is caused by germline mutation in the BAP1 gene (603089) on chromosome
3p21.

INHERITANCE

In connection with the etiology of mesothelioma, primary attention has
appropriately been focused on environmental factors, particularly
asbestos exposure. Li et al. (1978) reported pleural mesothelioma in the
wife and daughter of a man who worked for about 25 years as a pipe
insulator at a shipyard and who also developed pulmonary asbestosis and
lung cancer. The wife and daughter had no asbestos exposure other than
that from the man's clothing.

Risberg et al. (1980) described a family in Sweden in which the father,
3 brothers and a sister died of malignant mesothelioma. Four of the 5
probably had had asbestos exposure in the building industry. All were
smokers. The area showed low incidence of malignant mesothelioma. There
were 8 other sibs who were unaffected at the time of report (2 had died
of other causes). The authors suggested that, in addition to smoking and
asbestos, genetic factors may be involved in the pathogenesis.

Martensson et al. (1984) observed malignant mesothelioma in 2 pairs of
sibs and raised a question of a hereditary predisposing factor.

Although common household or occupational exposure may be responsible
for familial aggregation, Lynch et al. (1985) also raised the question
of a host factor in the occurrence and/or the histologic characteristics
of mesothelioma. They reported brothers who died of malignant pleural
mesothelioma.

Hammar et al. (1989) reported 3 brothers who worked in the asbestos
insulation business and developed mesothelioma. In a second family, a
father, who was occupationally exposed to asbestos, died from a
tubulopapillary peritoneal mesothelioma 11 years before his son died
from a peritoneal mesothelioma of identical histologic type. Although it
is possible that the son was secondarily exposed to asbestos from the
father's work clothes, quantitative asbestos analysis of the son's lung
tissue showed numbers of asbestos bodies well within the lower limits
seen in the general urban population with no occupational exposure to
asbestos. The simulation of mendelian dominant inheritance was indicated
by the occurrence of familial mesothelioma contracted as an infant by a
woman who died of this disorder at age 32.

A combination of asbestos exposure and host predisposition was suggested
also by the report of pleural malignant mesothelioma in 3 sisters and a
male cousin by Ascoli et al. (1998). The 3 women had worked in the same
confectionary shop as pastry cooks and/or pastry shop assistants; the
use of an asbestos-insulated oven was the putative source of exposure.
The man had occupational exposure as a heating system insulation worker.
Malignant cancers were reported in other relatives (larynx in a brother;
pleura and lung in a mother; lung in an aunt and uncle; and lung in a
cousin).

Erionite present in stones used to build the villages of Karain and
Tuzkoy, Turkey, mined from nearby caves, is purported to cause
mesothelioma in half of the villagers. Roushdy-Hammady et al. (2001)
constructed genetic epidemiology maps to test whether some villagers
were genetically predisposed to mesothelioma. Analysis of a 6-generation
extended pedigree of 526 individuals showed that mesothelioma was
genetically transmitted, probably in an autosomal dominant way. The
incidence of malignant mesothelioma in immigrants from Karain and Tuzkoy
living in Sweden and Germany was similar to or higher than that of the 2
Turkish villages, suggesting that erionite is only a cofactor in the
cause of malignant mesothelioma in genetically predisposed individuals.
This suggestion is supported by data showing an absence of mesothelioma
cases in the towns of Karlik and other nearby villages, whose houses
contain a similar amount of erionite.

Carbone and Testa (2001) claimed that genetic susceptibility to
mesothelioma in the Cappadocian region of Turkey was conclusively
demonstrated by the study of Roushdy-Hammady et al. (2001). Saracci and
Simonato (2001) presented several reasons why the study did not prove
genetic causation. One of the reasons was that before 1978, when endemic
mesothelioma was recognized in this area by the study of Baris et al.
(1978), mesothelioma was diagnosed as tuberculosis, lung cancer,
metastatic cancers, or other disorders. Some members of the family in
the reported pedigree must have died no later than 1960, long before
local recognition of the disease. Dogan et al. (2001) defended the
conclusion concerning a genetic factor for susceptibility to erionite
carcinogenicity. Saracci and Simonato (2001) pointed out that the
question has wide public health implications, given the weight that a
genetic factor may carry when debating liability in asbestos-related
mesotheliomas.

CYTOGENETICS

In 24 human malignant mesothelioma cell lines derived from untreated
primary tumors, Balsara et al. (1999) performed comparative genomic
hybridization analysis to identify chromosomal imbalances. Chromosomal
losses accounted for the majority of genomic imbalances. The most
frequent underrepresented segments were 22q (58%) and 15q11.1-q21 (54%).
To map more precisely the region of 15q deletion, loss of heterozygosity
analyses were performed with a panel of polymorphic microsatellite
markers distributed along 15q, which defined a minimal region of
chromosomal loss at 15q11.1-q15. Balsara et al. (1999) suggested that
this region harbors a putative tumor suppressor gene whose loss or
inactivation may contribute to the pathogenesis of many malignant
mesotheliomas.

Musti et al. (2002) described a family in which 3 sisters were affected
by malignant mesothelioma, 2 pleural and 1 peritoneal, and 1 brother was
affected by pleural plaques. All family members had been subjected to
previous asbestos exposure of environmental-residential type. For 13
years, from 1951 to 1964, their housing was provided by the father's
employer, an asbestos cement factory; the factory warehouse was on the
ground floor of the building in which they lived. DNA extracted from
paraffin-embedded malignant mesothelioma samples was used to search for
chromosomal alterations by comparative genomic hydridization (CGH). A
loss at chromosome 9p, a frequent event in malignant mesothelioma, was
the only change in 2 of the sisters, which suggested that this region
may be the site of 1 or more oncosuppressor genes that play an important
role in the development of the disease and in inducing greater genetic
susceptibility to the carcinogenic effects of asbestos.

MOLECULAR GENETICS

By immunohistochemical analysis of archival paraffin specimens and tumor
cell lines, Kratzke et al. (1995) found that p16(INK4) (CDKN2; 600160)
was expressed in a nonsmall cell lung cancer cell line but not in 12 of
12 primary thoracic mesotheliomas and 15 of 15 mesothelioma cell lines.
All tumor specimens and the tumor cell lines showed expression of
wildtype RB1 protein (614041). In addition, transfection of CDKN2
suppressed the growth of 2 independent mesothelioma cell lines. The
authors concluded that inactivation of the CDKN2 gene is an essential
step in the etiology of malignant mesotheliomas.

Baser et al. (2002) reported a patient with neurofibromatosis type II
(NF2; 101000) who developed malignant mesothelioma after a long
occupational exposure to asbestos. Genetic analysis of the tumor tissue
showed loss not only of chromosome 22, where the NF2 gene (607379) is
located, but also of chromosomes 14 and 15, and gain of chromosome 7.
Baser et al. (2002) suggested that an individual with a constitutional
mutation of an NF2 allele is more susceptible to mesothelioma. Although
mesothelioma is not a common feature in NF2, the authors cited the
observation of Knudson (1995) that somatic mutations of a tumor
suppressor gene, such as NF2, RB1, or p53 (191170), can be common in a
tumor type that is not characteristic of the hereditary disorder,
perhaps due to the proliferative timing of the cells involved.

By studying copy number alterations followed by candidate gene
sequencing of 53 primary malignant pleural mesothelioma (MPM) samples,
Bott et al. (2011) identified the BAP1 gene (603089) on chromosome
3p21.1 as a commonly somatically inactivated gene. Twelve (23%) of 53
tumors had nonsynonymous mutations, and 16 (30%) had at least single
copy genomic loss of the BAP1 locus. Tumors with mutations showed loss
of nuclear staining for BAP1. BAP1 losses were confirmed in an
independent collection of MPM tumors. The somatic nature of the
mutations was confirmed in all tumors that had matched normal tissue
available. Knockdown of BAP1 in mesothelioma cell lines expressing
wildtype BAP1 resulted in proliferation defects with an accumulation of
cells in S phase and also downregulated E2F (see, e.g.,
189971)-responsive genes. Given the known role of BAP1 in regulatory
ubiquitination of histones, the findings suggested transcriptional
deregulation as a pathogenic mechanism. Sequencing also confirmed
frequent inactivating mutations in the NF2 gene (11 of 53; 21%) and
identified previously undescribed missense mutations in the LATS2 gene
(604861) (2 of 53; 3.8%) and the LATS1 gene (603473) (2 of 53; 3.8%).

*FIELD* SA
Anderson et al. (1976); Li et al. (1989)
*FIELD* RF
1. Anderson, H. A.; Lilis, R.; Daum, S. M.; Fischbein, A. S.; Selikoff,
I. J.: Household-contact asbestos neoplastic risk. Ann. N.Y. Acad.
Sci. 271: 311-323, 1976.

2. Ascoli, V.; Scalzo, C. C.; Bruno, C.; Facciolo, F.; Lopergolo,
M.; Granone, P.; Nardi, F.: Familial pleural malignant mesothelioma:
clustering in three sisters and one cousin. Cancer Lett. 130: 203-207,
1998.

3. Balsara, B. R.; Bell, D. W.; Sonoda, G.; De Rienzo, A.; du Manoir,
S.; Jhanwar, S. C.; Testa, J. R.: Comparative genomic hybridization
and loss of heterozygosity analyses identify a common region of deletion
at 15q11.1-15 in human malignant mesothelioma. Cancer Res. 59: 450-454,
1999.

4. Baris, Y. I.; Sahin, A. A.; Ozesmi, M.; Kerse, I.; Ozen, E.; Kolacan,
B.; Altinors, A.; Goktepeli, A.: An outbreak of pleural mesothelioma
and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 33:
181-192, 1978.

5. Baser, M. E.; De Rienzo, A.; Altomare, D.; Balsara, B. R.; Hedrick,
N. M.; Gutmann, D. H.; Pitts, L. H.; Jackler, R. K.; Testa, J. R.
: Neurofibromatosis 2 and malignant mesothelioma. Neurology 59:
290-291, 2002.

6. Bott, M.; Brevet, M.; Taylor, B. S.; Shimizu, S.; Ito, T.; Wang,
L.; Creaney, J.; Lake, R. A.; Zakowski, M. F.; Reva, B.; Sander, C.;
Delsite, R.; Powell, S.; Zhou, Q.; Shen, R.; Olshen, A.; Rusch, V.;
Ladanyi, M.: The nuclear deubiquitinase BAP1 is commonly inactivated
by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nature
Genet. 43: 668-672, 2011.

7. Carbone, M.; Testa, J. R.: Genetic susceptibility and familial
malignant mesothelioma. (Letter) Lancet 357: 1804 only, 2001.

8. Dogan, A. U.; Baris, Y. I.; Emri, S.; Testa, J. R.; Carbone, M.
: Familial malignant mesothelioma: authors' reply. (Letter) Lancet 358:
1813-1814, 2001.

9. Hammar, S. P.; Bockus, D.; Remington, F.; Freidman, S.; LaZerte,
G.: Familial mesothelioma: a report of two families. Hum. Path. 20:
107-112, 1989.

10. Knudson, A.: Asbestos and mesothelioma: genetic lessons from
a tragedy. Proc. Nat. Acad. Sci. 92: 10819-10820, 1995.

11. Kratzke, R. A.; Otterson, G. A.; Lincoln, C. E.; Ewing, S.; Oie,
H.; Geradts, J.; Kaye, F. J.: Immunohistochemical analysis of the
p16(INK4) cyclin-dependent kinase inhibitor in malignant mesothelioma. J.
Nat. Cancer Inst. 87: 1870-1875, 1995.

12. Li, F. P.; Dreyfus, M. G.; Antman, K. H.: Asbestos-contaminated
nappies and familial mesothelioma. (Letter) Lancet 333: 909-910,
1989. Note: Originally Volume I.

13. Li, F. P.; Lokich, J.; Lapey, J.; Neptune, W. B.; Wilkins, E.
W., Jr.: Familial mesothelioma after intense asbestos exposure at
home. JAMA 240: 467 only, 1978.

14. Lynch, H. T.; Katz, D.; Markvicka, S. E.: Familial mesothelioma:
review and family study. Cancer Genet. Cytogenet. 15: 25-35, 1985.

15. Martensson, G.; Larsson, S.; Zettergre, L.: Malignant mesothelioma
in two pairs of siblings: is there a hereditary predisposing factor? Europ.
J. Resp. Dis. 65: 179-184, 1984.

16. Musti, M.; Cavone, D.; Aalto, Y.; Scattone, A.; Serio, G.; Knuutila,
S.: A cluster of familial malignant mesothelioma with del(9p) as
the sole chromosomal anomaly. Cancer Genet. Cytogenet. 138: 73-76,
2002.

17. Risberg, B.; Nickels, J.; Wagermark, J.: Familial clustering
of malignant mesothelioma. Cancer 45: 2422-2427, 1980.

18. Roushdy-Hammady, I.; Siegel, J.; Emri, S.; Testa, J. R.; Carbone,
M.: Genetic-susceptibility factor and malignant mesothelioma in the
Cappadocian region of Turkey. Lancet 357: 444-445, 2001.

19. Saracci, R.; Simonato, L.: Familial malignant mesothelioma. (Letter) Lancet 358:
1813 only, 2001.

*FIELD* CS

Oncology:
Malignant mesothelioma

Inheritance:
Hereditary predisposing factor

*FIELD* CN
Cassandra L. Kniffin - updated: 8/8/2011
Patricia A. Hartz - updated: 1/15/2004
Victor A. McKusick - updated: 1/10/2003
Cassandra L. Kniffin - updated: 10/3/2002
Victor A. McKusick - updated: 2/14/2002
Ada Hamosh - updated: 4/26/2001
Victor A. McKusick - updated: 3/24/1999
Victor A. McKusick - updated: 2/19/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
joanna: 12/20/2011
carol: 12/15/2011
carol: 11/9/2011
ckniffin: 11/8/2011
ckniffin: 11/3/2011
wwang: 8/12/2011
ckniffin: 8/8/2011
carol: 6/17/2011
terry: 6/3/2009
terry: 1/30/2009
joanna: 3/18/2004
mgross: 1/15/2004
carol: 1/28/2003
tkritzer: 1/15/2003
terry: 1/10/2003
carol: 10/21/2002
ckniffin: 10/3/2002
terry: 6/27/2002
carol: 2/20/2002
cwells: 2/15/2002
terry: 2/14/2002
mcapotos: 5/7/2001
terry: 4/26/2001
kayiaros: 7/8/1999
mgross: 4/2/1999
mgross: 3/30/1999
terry: 3/24/1999
carol: 2/22/1999
terry: 2/19/1999
mimadm: 11/6/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 5/18/1989
carol: 4/3/1989

MIM 603517
*RECORD*
*FIELD* NO
603517
*FIELD* TI
*603517 B-CELL CLL/LYMPHOMA 10; BCL10
;;B-CELL LEUKEMIA/LYMPHOMA 10
*FIELD* TX

CLONING
read more
B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas)
are the most common form of lymphoma arising in extranodal sites, in
most cases arising in the gastric mucosa (Isaacson and Spencer, 1995).
Cytogenetic studies of low-grade malignant MALT lymphoma identified
abnormalities of chromosome 1p22, in particular translocation
t(1;14)(p22;q32), as uncommon but recurrent events (Wotherspoon et al.,
1992). Willis et al. (1999) cloned a t(1;14)(p22;q32) translocation
breakpoint from a case of low-grade MALT lymphoma and identified a
recurrent breakpoint upstream of the promoter of a novel gene, BCL10.
The BCL10 gene encodes a predicted protein of 233 amino acids and is a
cellular homolog of the equine herpesvirus-2 gene (E10); both contain an
amino-terminal caspase recruitment domain (CARD) homologous to that
found in several apoptotic molecules. BCL10 was found to be expressed as
a transcript of 4.2 kb in all normal and malignant tissues examined.

GENE FUNCTION

Willis et al. (1999) found that BCL10 and E10 activated nuclear factor
kappa-B (NFKB; 164011) but caused apoptosis of 293 cells.

Thome et al. (1999) characterized the E10 gene product and its cellular
homolog, BCL10, which they designated viral and cellular CARMEN
(CARD-containing molecule enhancing NFKB), respectively. Although the
viral and cellular proteins each contain an N-terminal CARD domain
through which they interact, they diverge in their C-terminal
extensions. They determined that only the viral E10 protein binds to
TRAF6 (602355) and, upon overexpression, induces JNK (601158) and NFKB
activation. They found that BCL10 does not affect the activating
potential of the viral protein.

Using biochemical and genetic approaches, Wegener et al. (2006)
demonstrated that IKKB (IKBKB; 603258) is critical for regulation of the
CARMA1 (CARD11; 607210)-BCL10-MALT1 (604860) (CBM) complex. They found
that IKKB is required not only for initial complex formation, but also
for triggering disengagement of BCL10 and MALT1 by phosphorylation of
the C terminus of BCL10, thereby negatively influencing T-cell receptor
signaling. Wegener et al. (2006) proposed a model in which IKKB is
associated with BCL10-MALT1 in resting T cells. Following T-cell
activation, protein kinase C-theta (PRKCQ; 600448) phosphorylates CARMA1
and induces association of CARMA1 with BCL10-MALT1. Formation of the BCM
complex induces maximal activation of IKK through activation of IKKG
(IKBKG; 300248). IKKB phosphorylates BCL10 in its MALT1 interaction
domain, causing BCL10 and MALT1 to disassociate, resulting in
attenuation of NFKB signaling and cytokine production.

MAPPING

Willis et al. (1999) mapped the BCL10 gene to chromosome 1p22.

MOLECULAR GENETICS

Willis et al. (1999) found that BCL10 expressed in a B-cell lymphoma of
mucosa-associated lymphoid tissue (MALT lymphoma) exhibited a frameshift
mutation resulting in truncation distal to the CARD. Truncated BCL10
activated NFKB but did not induce apoptosis. Wildtype BCL10 suppressed
transformation, whereas mutant forms had lost this activity and
displayed gain-of-function transforming activity. PCR-SSCP analysis of a
panel of 135 cases of B-cell and 20 cases of T-cell lineage lymphoma of
various histologic subtypes revealed abnormal migrating bands in 70
(45%). The sequence abnormalities in 10 such cases of MALT lymphoma and
follicular non-Hodgkin lymphoma revealed truncating BCL10 mutations in
both subtypes in the absence of 1p22 chromosomal translocation.
Eighty-seven cell lines derived from patients with other forms of
malignancy were examined for BCL10 mutations. All 3 mesothelioma
(156240) and all 3 male germ cell tumor (TGCT; 273300) cell lines
exhibited BCL10 mutations, whereas no mutations were seen in a panel of
15 breast carcinoma (114480), 11 pancreatic adenocarcinoma (260350), and
15 lung carcinoma cell lines. BCL10 mutations were seen in 2 of 25
colonic adenocarcinoma (114500) and 2 of 18 leukemia and lymphoma cell
lines. Willis et al. (1999) concluded that BCL10 may commonly be
involved in the pathogenesis of human malignancy.

Fakruddin et al. (1999) performed mutation analysis of the BCL10 coding
region in a panel of 59 male germ cell tumors (MGCTs; 41 primary tumors
and 18 cell lines, including the same 3 cell lines previously studied by
Willis et al., 1999), 15 MALT lymphomas, and 15 follicular lymphomas.
Conformation changes detected by SSCP in both MGCTs and lymphomas were
then analyzed in paired normal-tumor DNAs by SSCP; identical SSCP
variants were found in all cases, suggesting that these represented
genetic polymorphisms. Sequencing of BCL10 in the 3 MGCT cell lines
previously studied by Willis et al. (1999) revealed no mutations.
Fakruddin et al. (1999) noted that their data were at variance with the
results reported by Willis et al. (1999), and concluded that BCL10 is
not a target tumor suppressor gene at 1p22 in MGCTs or B-cell lymphomas.

Van Schothorst et al. (1999) screened exons 2 and 3 of the BCL10 gene in
a series of TGCT-derived and related cell lines, including the 3 GCT
cell lines previously studied by Willis et al. (1999), as well as
primary tumors. No aberrations were detected by SSCP on genomic DNA or
restriction endonuclease digestion analysis of PCR-amplified fragments.
Van Schothorst et al. (1999) concluded that inactivation of BCL10 by
genomic events in TGCTs is not involved in the majority of cases, if at
all.

Lee et al. (1999) analyzed the BCL10 gene by PCR-SSCP using DNA
extracted from malignant and normal cells of 439 paraffin-embedded tumor
tissue samples, including 120 malignant lymphomas and 78 GCTs.
Enrichment and direct sequencing of aberrantly migrating bands led to
the identification of somatic mutations in 6 (1.4%) of the 439 samples:
4 (3.3%) of 120 malignant lymphomas, including 2 diffuse large B-cell
lymphomas (DLBCLs), 1 MALT lymphoma, and 1 angiocentric T-cell lymphoma,
and 2 (2.6%) of 78 TGCTs (both were mature teratomas; see, e.g.,
603517.0018). No mutations were found in the other solid tumors
analyzed, which included malignant mesotheliomas, laryngeal squamous
cell carcinomas, breast, gastric, hepatocellular, and colorectal
adenocarcinomas. Lee et al. (1999) concluded that BCL10 may occasionally
be involved in the pathogenesis of lymphoma and TGCTs, but that the
absence or low frequency of mutation suggested that either BCL10 is
inactivated by other mechanisms or that it is not the only target of
chromosome 1p22 deletion in human tumors.

Kakinuma et al. (2001) found loss of heterozygosity at chromosome 1p in
21 (42%) of 49 Japanese TGCTs, including 12 (43%) of 28 seminomas and 8
(38%) of 21 nonseminomatous GCTs. No somatic mutations were identified
by SSCP and direct sequencing in any of the tumors, although 4 SNPs were
detected.

Inoue et al. (2006) analyzed 4 BCL10 SNPs, previously identified in
Japanese TGCTs by Kakinuma et al. (2001), in 73 TGCT patients and 72
controls. No significant difference in any of the 4 SNPs was observed
between patients and controls. However, GCT patients with metastatic
disease were more likely than patients with only local disease to carry
a minor allele of either of 2 SNPs in exon 1: 13G-T (A5S; adjusted odds
ratio, 6.25, and p = 0.040) or 24C-G (L8L; adjusted odds ratio, 4.63,
and p = 0.015). Inoue et al. (2006) concluded that these BCL10
polymorphisms in exon 1 might play a role in progression to advanced
stage TGCTs.

ANIMAL MODEL

Ruland et al. (2001) showed that one-third of Bcl10 -/- mouse embryos
developed exencephaly, leading to embryonic lethality. Surprisingly,
Bcl10 -/- cells retained susceptibility to various apoptotic stimuli in
vivo and in vitro. However, surviving Bcl10 -/- mice were severely
immunodeficient, and Bcl10 -/- lymphocytes were defective in antigen
receptor or phorbol myristate acetate (PMA)/ionomycin-induced
activation. Early tyrosine phosphorylation, mitogen-activated protein
kinase (MAPK; see 604921) and activator protein-1 (AP1; 165160)
activation, and calcium signaling were normal in mutant lymphocytes, but
antigen receptor-induced NFKB activation was absent. Thus, the authors
concluded that BCL10 functions as a positive regulator of lymphocyte
proliferation that specifically connects antigen receptor signaling in B
and T cells to NFKB activation.

By disrupting exon 3 of the Bcl10 gene, which encodes the CARD domain,
Xue et al. (2003) generated healthy, fertile mice lacking Bcl10. Flow
cytometric and immunohistochemical analyses demonstrated a reduction in
the number of follicular, marginal zone, and B1 B cells. Follicular and
marginal zone B cells were unable to proliferate, and marginal zone B
cells were unable to activate Nfkb in response to lipopolysaccharide.
Mutant mice did not survive infection with Streptococcus pneumoniae. Xue
et al. (2003) concluded that BCL10 is essential for the development of
all mature B-cell subsets.

*FIELD* AV
.0001
MALT LYMPHOMA, SOMATIC
MESOTHELIOMA, SOMATIC, INCLUDED;;
MALE GERM CELL TUMOR, SOMATIC, INCLUDED
BCL10, 1-BP INS, 499T

In 2 cases of MALT lymphoma (137245), the M25 cell line from a patient
with mesothelioma (156240), and the Tera-2 testicular germ cell tumor
cell line (273300), Willis et al. (1999) found a 499insT mutation
causing a frameshift at codon 167 of BCL10.

Fakruddin et al. (1999) sequenced BCL10 in the Tera-2 GCT cell line,
previously studied by Willis et al. (1999), but found no mutations.

Van Schothorst et al. (1999) screened exons 2 and 3 of the BCL10 gene in
the Tera-2 GCT cell line and mesothelioma-derived cell line M25, both
previously studied by Willis et al. (1999) and found to carry the
499insT mutation. No aberrations were detected by SSCP on genomic DNA or
restriction endonuclease digestion analysis of PCR-amplified fragments.

.0002
MALT LYMPHOMA, SOMATIC
BCL10, 1-BP INS, 163A

In a case of MALT lymphoma (137245), Willis et al. (1999) found a
163insA mutation causing a frameshift at codon 55 of BCL10.

.0003
MALT LYMPHOMA, SOMATIC
BCL10, 1-BP DEL, 345A

In 2 cases of MALT lymphoma (137245), Willis et al. (1999) found a
345delA mutation causing a frameshift at codon 115 of BCL10.

.0004
FOLLICULAR LYMPHOMA, SOMATIC
BCL10, 2-BP INS, 428TT

In a case of follicular lymphoma (605207), Willis et al. (1999) found a
428insTT mutation causing a frameshift at codon 143 of BCL10.

.0005
FOLLICULAR LYMPHOMA, SOMATIC
BCL10, 1-BP INS, 231A

In a case of follicular lymphoma (605207), Willis et al. (1999) found a
231insA mutation causing a frameshift at codon 77 of BCL10.

.0006
FOLLICULAR LYMPHOMA, SOMATIC
BCL10, 17-BP DEL, NT525

In a case of follicular lymphoma (605207), Willis et al. (1999) found a
525del17 mutation causing a frameshift at codon 175 of BCL10.

.0007
FOLLICULAR LYMPHOMA, SOMATIC
BCL10, 1-BP DEL, 410A

In a case of follicular lymphoma (605207), Willis et al. (1999) found a
410delA mutation causing a frameshift at codon 137 of BCL10.

.0008
FOLLICULAR LYMPHOMA, SOMATIC
BCL10, 1-BP INS, 398T

In a case of follicular lymphoma (605207), Willis et al. (1999) found a
398insT mutation causing a frameshift at codon 133 of BCL10.

.0009
FOLLICULAR LYMPHOMA, SOMATIC
BCL10, 3-BP DEL, GLU210DEL

In a case of follicular lymphoma (605207), Willis et al. (1999) found a
3-bp deletion resulting in deletion of glu210 of BCL10.

.0010
T-CELL ACUTE LYMPHOCYTIC LEUKEMIA, SOMATIC
COLON CANCER, SOMATIC, INCLUDED
BCL10, 1-BP INS, 136A

In a cell line from a patient with T-cell acute lymphocytic leukemia
(see 613065) and a cell line from a patient with colon cancer (114500),
Willis et al. (1999) found a 136insA mutation causing a frameshift at
codon 46 of BCL10.

.0011
SEZARY SYNDROME, SOMATIC
BCL10, 1-BP DEL, 428T

In a cell line from a patient with Sezary syndrome, Willis et al. (1999)
found a 428delT mutation causing a frameshift at codon 143 of BCL10.

.0012
MOVED TO 603517.0010
.0013
MOVED TO 603517.0001
.0014
MESOTHELIOMA, SOMATIC
BCL10, 1-BP DEL, 136A

In a cell line from a patient with mesothelioma (156240), Willis et al.
(1999) found a 136delA mutation causing a frameshift at codon 43 of
BCL10.

.0015
MOVED TO 603517.0001
.0016
MALE GERM CELL TUMOR, SOMATIC
BCL10, ARG58GLY

In the Tera-1 cell line from a patient with germ cell tumor, Willis et
al. (1999) found a 172C-G transversion in exon 2 of the BCL10 gene,
resulting in an arg58-to-gly (R58G) mutation.

.0017
MALE GERM CELL TUMOR, SOMATIC
BCL10, ARG58TER

In the GCT-44 cell line from a patient with germ cell tumor, Willis et
al. (1999) found a 172C-T transition in exon 2 of the BCL10 gene,
resulting in an arg58-to-ter (R58X) substitution.

Fakruddin et al. (1999) sequenced BCL10 in the GCT-44 cell line,
previously studied by Willis et al. (1999), but found no mutations.

Van Schothorst et al. (1999) screened exons 2 and 3 of the BCL10 gene in
the GCT-44 cell line but detected no aberrations by SSCP on genomic DNA
or restriction endonuclease digestion analysis of PCR-amplified
fragments.

.0018
TESTICULAR TERATOMA, SOMATIC
BCL10, THR161MET

In malignant cells procured from paraffin-embedded tissue from a mature
testicular teratoma (see 273300), Lee et al. (1999) identified a 588C-T
transition in exon 3 of the BCL10 gene, resulting in a thr161-to-met
(T161M) substitution.

*FIELD* RF
1. Fakruddin, J. M.; Chaganti, R. S. K.; Murty, V. V. V. S.: Lack
of BCL10 mutations in germ cell tumors and B cell lymphomas. Cell 97:
683-688, 1999.

2. Inoue, T.; Ito, T.; Narita, S.; Horikawa, Y.; Tsuchiya, N.; Kakinuma,
H.; Mishina, M.; Nakamura, E.; Kato, T.; Ogawa, O.; Habuchi, T.:
Association of BCL10 germ line polymorphisms on chromosome 1p with
advanced stage testicular germ cell tumor patients. Cancer Lett. 240:
41-47, 2006.

3. Isaacson, P. G.; Spencer, J.: The biology of low grade MALT lymphoma. J.
Clin. Path. 48: 395-397, 1995.

4. Kakinuma, H.; Habuchi, T.; Ito, T.; Mishina, M.; Sato, K.; Satoh,
S.; Akao, T.; Ogawa, O.; Kato, T.: BCL10 is not a major target for
frequent loss of 1p in testicular germ cell tumors. Cancer Genet.
Cytogenet. 126: 134-138, 2001.

5. Lee, S. H.; Shin, M. S.; Kim, H. S.; Park, W. S.; Kim, S. Y.; Lee,
H. K.; Park, J. Y.; Oh, R. R.; Jang, J. J.; Park, K. M.; Han, J. Y.;
Kang, C. S.; Lee, J. Y.; Yoo, N. J.: Point mutations and deletions
of the Bcl10 gene in solid tumors and malignant lymphomas. Cancer
Res. 59: 5674-5677, 1999.

6. Ruland, J.; Duncan, G. S.; Elia, A.; del Barco Barrantes, I.; Nguyen,
L.; Plyte, S.; Millar, D. G.; Bouchard, D.; Wakeham, A.; Ohashi, P.
S.; Mak, T. W.: Bcl10 is a positive regulator of antigen receptor-induced
activation of NF-kappa-B and neural tube closure. Cell 104: 33-42,
2001.

7. Thome, M.; Martinon, F.; Hofmann, K.; Rubio, V.; Steiner, V.; Schneider,
P.; Mattmann, C.; Tschopp, J.: Equine herpesvirus-2 E10 gene product,
but not its cellular homologue, activates NF-kappa-B transcription
factor and c-Jun N-terminal kinase. J. Biol. Chem. 274: 9962-9968,
1999.

8. van Schothorst, E. M.; Mohkamsing, S.; van Gurp, R. J. H. L. M.;
Oosterhuis, J. W.; van der Saag, P. T.; Looijenga, L. H. J.: Lack
of Bcl10 mutations in testicular germ cell tumours and derived cell
lines. Brit. J. Cancer 80: 1571-1574, 1999.

9. Wegener, E.; Oeckinghaus, A.; Papadopoulou, N.; Lavitas, L.; Schmidt-Supprian,
M.; Ferch, U.; Mak, T. W.; Ruland, J.; Heissmeyer, V.; Krappmann,
D.: Essential role for I-kappa-B kinase beta in remodeling Carma1-Bcl10-Malt1
complexes upon T cell activation. Molec. Cell 23: 13-23, 2006.

10. Willis, T. G.; Jadayel, D. M.; Du, M.-Q.; Peng, H.; Perry, A.
R.; Abdul-Rauf, M.; Price, H.; Karran, L.; Majekodunmi, O.; Wlodarska,
I.; Pan, L.; Crook, T.; Hamoudi, R.; Isaacson, P. G.; Dyer, M. J.
S.: Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma
and mutated in multiple tumor types Cell 96: 35-45, 1999.

11. Wotherspoon, A. C.; Pan, L. X.; Diss, T. C.; Isaacson, P. G.:
Cytogenetic study of B-cell lymphoma of mucosa-associated lymphoid
tissue. Cancer Genet. Cytogenet. 58: 35-38, 1992.

12. Xue, L.; Morris, S. W.; Orihuela, C.; Tuomanen, E.; Cui, X.; Wen,
R.; Wang, D.: Defective development and function of Bcl10-deficient
follicular, marginal zone and B1 B cells. Nature Immun. 4: 857-865,
2003.

*FIELD* CN
Marla J. F. O'Neill - updated: 11/23/2011
Paul J. Converse - updated: 8/22/2006
Paul J. Converse - updated: 9/8/2003
Paul J. Converse - updated: 4/11/2002
Stylianos E. Antonarakis - updated: 1/7/2002
Stylianos E. Antonarakis - updated: 2/1/2001
Jane Kelly - updated: 6/23/2000

*FIELD* CD
Stylianos E. Antonarakis: 2/11/1999

*FIELD* ED
carol: 11/23/2011
carol: 11/17/2011
ckniffin: 8/8/2011
ckniffin: 10/5/2009
mgross: 8/22/2006
alopez: 9/11/2003
mgross: 9/8/2003
mgross: 4/11/2002
mgross: 4/10/2002
mgross: 1/7/2002
terry: 6/4/2001
mgross: 2/1/2001
alopez: 6/23/2000
mgross: 3/10/1999
mgross: 2/12/1999