RBCC Red Blood Cell Collection

CASP3 (CPP32) [Confidence: low (only semi-automatic identification from reviews)]
Caspase-3; CASP-3; 3.4.22.56 (Apopain; Cysteine protease CPP32; CPP-32; Protein Yama; SREBP cleavage activity 1; SCA-1; Caspase-3 subunit p17; Caspase-3 subunit p12; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P42574
ID CASP3_HUMAN Reviewed; 277 AA.
AC P42574; A8K5M2; D3DP53; Q96AN1; Q96KP2;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-OCT-2005, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Caspase-3;
DE Short=CASP-3;
DE EC=3.4.22.56;
DE AltName: Full=Apopain;
DE AltName: Full=Cysteine protease CPP32;
DE Short=CPP-32;
DE AltName: Full=Protein Yama;
DE AltName: Full=SREBP cleavage activity 1;
DE Short=SCA-1;
DE Contains:
DE RecName: Full=Caspase-3 subunit p17;
DE Contains:
DE RecName: Full=Caspase-3 subunit p12;
DE Flags: Precursor;
GN Name=CASP3; Synonyms=CPP32;
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], AND VARIANT ASP-190.
RC TISSUE=T-cell;
RX PubMed=7983002;
RA Fernandes-Alnemri T., Litwack G., Alnemri E.S.;
RT "CPP32, a novel human apoptotic protein with homology to
RT Caenorhabditis elegans cell death protein Ced-3 and mammalian
RT interleukin-1 beta-converting enzyme.";
RL J. Biol. Chem. 269:30761-30764(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7774019; DOI=10.1016/0092-8674(95)90541-3;
RA Tewari M., Quan L.T., O'Rourke K., Desnoyers S., Zeng Z.,
RA Beidler D.R., Poirier G.G., Salvesen G.S., Dixit V.M.;
RT "Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable
RT protease that cleaves the death substrate poly(ADP-ribose)
RT polymerase.";
RL Cell 81:801-809(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASP-190.
RX PubMed=15003516; DOI=10.1016/j.bbrc.2004.02.021;
RA Pelletier M., Cartron P.F., Delaval F., Meflah K., Vallette F.M.,
RA Oliver L.;
RT "Caspase 3 activation is controlled by a sequence located in the N-
RT terminus of its large subunit.";
RL Biochem. Biophys. Res. Commun. 316:93-99(2004).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [8]
RP PROTEIN SEQUENCE OF 29-46 AND 175-193, FUNCTION, AND VARIANT ASP-190.
RX PubMed=7596430; DOI=10.1038/376037a0;
RA Nicholson D.W., Ali A., Thornberry N.A., Vaillancourt J.P., Ding C.K.,
RA Gallant M., Gareau Y., Griffin P.R., Labelle M., Lazebnik Y.A.,
RA Munday N.A., Raju S.M., Smulson M.E., Yamin T.-T., Li V.L.,
RA Miller D.K.;
RT "Identification and inhibition of the ICE/CED-3 protease necessary for
RT mammalian apoptosis.";
RL Nature 376:37-43(1995).
RN [9]
RP PROTEOLYTIC PROCESSING.
RX PubMed=8755496; DOI=10.1073/pnas.93.15.7464;
RA Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M.,
RA Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J.,
RA Litwack G., Alnemri E.S.;
RT "In vitro activation of CPP32 and Mch3 by Mch4, a novel human
RT apoptotic cysteine protease containing two FADD-like domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996).
RN [10]
RP CLEAVAGE OF HUNTINGTIN.
RX PubMed=8696339; DOI=10.1038/ng0896-442;
RA Goldberg Y.P., Nicholson D.W., Rasper D.M., Kalchman M.A., Koide H.B.,
RA Graham R.K., Bromm M., Kazemi-Esfarjani P., Thornberry N.A.,
RA Vaillancourt J.P., Hayden M.R.;
RT "Cleavage of huntingtin by apopain, a proapoptotic cysteine protease,
RT is modulated by the polyglutamine tract.";
RL Nat. Genet. 13:442-449(1996).
RN [11]
RP S-NITROSYLATION.
RX PubMed=10213689; DOI=10.1126/science.284.5414.651;
RA Mannick J.B., Hausladen A., Liu L., Hess D.T., Zeng M., Miao Q.X.,
RA Kane L.S., Gow A.J., Stamler J.S.;
RT "Fas-induced caspase denitrosylation.";
RL Science 284:651-654(1999).
RN [12]
RP INTERACTION WITH BIRC6/BRUCE.
RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018;
RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.;
RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3
RT ubiquitin ligase.";
RL Mol. Cell 14:801-811(2004).
RN [13]
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 [14]
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 [15]
RP FUNCTION IN CELL ADHESION.
RX PubMed=21357690; DOI=10.1074/jbc.M110.195461;
RA Cabrera J.R., Bouzas-Rodriguez J., Tauszig-Delamasure S., Mehlen P.;
RT "RET modulates cell adhesion via its cleavage by caspase in
RT sympathetic neurons.";
RL J. Biol. Chem. 286:14628-14638(2011).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 28-277.
RX PubMed=8673606; DOI=10.1038/nsb0796-619;
RA Rotonda J., Nicholson D.W., Fazil K.M., Gallant M., Gareau Y.,
RA Labelle M., Peterson E.P., Rasper D.M., Ruel R., Vaillancourt J.P.,
RA Thornberry N.A., Becker J.W.;
RT "The three-dimensional structure of apopain/CPP32, a key mediator of
RT apoptosis.";
RL Nat. Struct. Biol. 3:619-625(1996).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 35-173 AND 185-277.
RX PubMed=9045680; DOI=10.1074/jbc.272.10.6539;
RA Mittl P.R.E., di Marco S., Krebs J.F., Bai X., Karanewsky D.S.,
RA Priestle J.P., Tomaselli K.J., Gruetter M.G.;
RT "Structure of recombinant human CPP32 in complex with the tetrapeptide
RT acetyl-Asp-Val-Ala-Asp fluoromethyl ketone.";
RL J. Biol. Chem. 272:6539-6547(1997).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
RX PubMed=10821855; DOI=10.1074/jbc.275.21.16007;
RA Lee D., Long S.A., Adams J.L., Chan G., Vaidya K.S., Francis T.A.,
RA Kikly K., Winkler J.D., Sung C.-M., Debouck C., Richardson S.,
RA Levy M.A., DeWolf W.E. Jr., Keller P.M., Tomaszek T., Head M.S.,
RA Ryan M.D., Haltiwanger R.C., Liang P.-H., Janson C.A., McDevitt P.J.,
RA Johanson K., Concha N.O., Chan W., Abdel-Meguid S.S., Badger A.M.,
RA Lark M.W., Nadeau D.P., Suva L.J., Gowen M., Nuttall M.E.;
RT "Potent and selective nonpeptide inhibitors of caspases 3 and 7
RT inhibit apoptosis and maintain cell functionality.";
RL J. Biol. Chem. 275:16007-16014(2000).
CC -!- FUNCTION: Involved in the activation cascade of caspases
CC responsible for apoptosis execution. At the onset of apoptosis it
CC proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a
CC '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory
CC element binding proteins (SREBPs) between the basic helix-loop-
CC helix leucine zipper domain and the membrane attachment domain.
CC Cleaves and activates caspase-6, -7 and -9. Involved in the
CC cleavage of huntingtin. Triggers cell adhesion in sympathetic
CC neurons through RET cleavage.
CC -!- CATALYTIC ACTIVITY: Strict requirement for an Asp residue at
CC positions P1 and P4. It has a preferred cleavage sequence of Asp-
CC Xaa-Xaa-Asp-|- with a hydrophobic amino-acid residue at P2 and a
CC hydrophilic amino-acid residue at P3, although Val or Ala are also
CC accepted at this position.
CC -!- ENZYME REGULATION: Inhibited by isatin sulfonamides.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel
CC arranged heterodimers, each one formed by a 17 kDa (p17) and a 12
CC kDa (p12) subunit. Interacts with BIRC6/bruce.
CC -!- INTERACTION:
CC Q9BYP7:WNK3; NbExp=2; IntAct=EBI-524064, EBI-1182602;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Highly expressed in lung, spleen, heart, liver
CC and kidney. Moderate levels in brain and skeletal muscle, and low
CC in testis. Also found in many cell lines, highest expression in
CC cells of the immune system.
CC -!- PTM: Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10
CC generates the two active subunits. Additional processing of the
CC propeptides is likely due to the autocatalytic activity of the
CC activated protease. Active heterodimers between the small subunit
CC of caspase-7 protease and the large subunit of caspase-3 also
CC occur and vice versa.
CC -!- PTM: S-nitrosylated on its catalytic site cysteine in unstimulated
CC human cell lines and denitrosylated upon activation of the Fas
CC apoptotic pathway, associated with an increase in intracellular
CC caspase activity. Fas therefore activates caspase-3 not only by
CC inducing the cleavage of the caspase zymogen to its active
CC subunits, but also by stimulating the denitrosylation of its
CC active site thiol.
CC -!- SIMILARITY: Belongs to the peptidase C14A family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/casp3/";
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DR EMBL; U13737; AAA65015.1; -; mRNA.
DR EMBL; U13738; AAB60355.1; -; mRNA.
DR EMBL; U26943; AAA74929.1; -; mRNA.
DR EMBL; AJ413269; CAC88866.1; -; mRNA.
DR EMBL; AK291337; BAF84026.1; -; mRNA.
DR EMBL; AY219866; AAO25654.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04673.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04674.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04675.1; -; Genomic_DNA.
DR EMBL; BC016926; AAH16926.1; -; mRNA.
DR PIR; A55315; A55315.
DR RefSeq; NP_004337.2; NM_004346.3.
DR RefSeq; NP_116786.1; NM_032991.2.
DR UniGene; Hs.141125; -.
DR PDB; 1CP3; X-ray; 2.30 A; A/B=1-277.
DR PDB; 1GFW; X-ray; 2.80 A; A=29-175, B=181-277.
DR PDB; 1I3O; X-ray; 2.70 A; A/C=1-175, B/D=176-277.
DR PDB; 1NME; X-ray; 1.60 A; A=29-174, B=186-277.
DR PDB; 1NMQ; X-ray; 2.40 A; A/B=29-277.
DR PDB; 1NMS; X-ray; 1.70 A; A/B=29-277.
DR PDB; 1PAU; X-ray; 2.50 A; A=29-175, B=176-277.
DR PDB; 1QX3; X-ray; 1.90 A; A=29-277.
DR PDB; 1RE1; X-ray; 2.50 A; A=29-175, B=176-277.
DR PDB; 1RHJ; X-ray; 2.20 A; A/C=29-175, B/D=176-277.
DR PDB; 1RHK; X-ray; 2.50 A; A=29-175, B=176-277.
DR PDB; 1RHM; X-ray; 2.50 A; A/C=29-175, B/D=176-277.
DR PDB; 1RHQ; X-ray; 3.00 A; A/D=29-175, B/E=176-277.
DR PDB; 1RHR; X-ray; 3.00 A; A=29-175, B=176-277.
DR PDB; 1RHU; X-ray; 2.51 A; A=29-175, B=176-277.
DR PDB; 2C1E; X-ray; 1.77 A; A=29-175, B=176-277.
DR PDB; 2C2K; X-ray; 1.87 A; A=29-175, B=176-277.
DR PDB; 2C2M; X-ray; 1.94 A; A=29-175, B=176-277.
DR PDB; 2C2O; X-ray; 2.45 A; A=29-175, B=176-277.
DR PDB; 2CDR; X-ray; 1.70 A; A=29-175, B=176-277.
DR PDB; 2CJX; X-ray; 1.70 A; A=29-175, B=176-277.
DR PDB; 2CJY; X-ray; 1.67 A; A=29-175, B=176-277.
DR PDB; 2CNK; X-ray; 1.75 A; A=29-175, B=176-277.
DR PDB; 2CNL; X-ray; 1.67 A; A=29-175, B=176-277.
DR PDB; 2CNN; X-ray; 1.70 A; A=29-175, B=176-277.
DR PDB; 2CNO; X-ray; 1.95 A; A=29-175, B=176-277.
DR PDB; 2DKO; X-ray; 1.06 A; A=29-174, B=176-277.
DR PDB; 2H5I; X-ray; 1.69 A; A=29-174, B=184-277.
DR PDB; 2H5J; X-ray; 2.00 A; A/C=29-174, B/D=184-277.
DR PDB; 2H65; X-ray; 2.30 A; A/C=29-174, B/D=184-277.
DR PDB; 2J30; X-ray; 1.40 A; A=29-277.
DR PDB; 2J31; X-ray; 1.50 A; A=29-277.
DR PDB; 2J32; X-ray; 1.30 A; A=29-277.
DR PDB; 2J33; X-ray; 2.00 A; A=29-277.
DR PDB; 2XYG; X-ray; 1.54 A; A=29-174, B=185-277.
DR PDB; 2XYH; X-ray; 1.89 A; A=29-174, B=185-277.
DR PDB; 2XYP; X-ray; 1.86 A; A=29-174, B=185-277.
DR PDB; 2XZD; X-ray; 2.10 A; A/C=29-175, B/D=176-277.
DR PDB; 2XZT; X-ray; 2.70 A; A/C=29-175, B/D=176-277.
DR PDB; 2Y0B; X-ray; 2.10 A; A/C=29-175, B/D=176-277.
DR PDB; 3DEH; X-ray; 2.50 A; A/B/C/D=29-277.
DR PDB; 3DEI; X-ray; 2.80 A; A/B/C/D=29-277.
DR PDB; 3DEJ; X-ray; 2.60 A; A/B/C/D=29-277.
DR PDB; 3DEK; X-ray; 2.40 A; A/B/C/D=29-277.
DR PDB; 3EDQ; X-ray; 1.61 A; A/C=29-175, B/D=176-277.
DR PDB; 3GJQ; X-ray; 2.60 A; A/C=29-175, B/D=176-277.
DR PDB; 3GJR; X-ray; 2.20 A; A/C=29-175, B/D=176-277.
DR PDB; 3GJS; X-ray; 1.90 A; A/C=29-175, B/D=176-277.
DR PDB; 3GJT; X-ray; 2.20 A; A/C=29-175, B/D=176-277.
DR PDB; 3H0E; X-ray; 2.00 A; A/B=29-277.
DR PDB; 3ITN; X-ray; 1.63 A; A=29-277.
DR PDB; 3KJF; X-ray; 2.00 A; A=29-175, B=176-277.
DR PDB; 3PCX; X-ray; 1.50 A; A=29-277.
DR PDB; 3PD0; X-ray; 2.00 A; A=29-277.
DR PDB; 3PD1; X-ray; 1.62 A; A=29-277.
DR PDB; 4DCJ; X-ray; 1.70 A; A/D=29-175, B/E=176-277.
DR PDB; 4DCO; X-ray; 1.70 A; A/D=29-175, B/E=176-277.
DR PDB; 4DCP; X-ray; 1.70 A; A/D=29-175, B/E=176-277.
DR PDB; 4EHA; X-ray; 1.70 A; A/C=1-277.
DR PDB; 4EHD; X-ray; 1.58 A; A=1-277.
DR PDB; 4EHF; X-ray; 1.66 A; A=1-277.
DR PDB; 4EHH; X-ray; 1.78 A; A=1-277.
DR PDB; 4EHK; X-ray; 1.67 A; A/C=1-277.
DR PDB; 4EHL; X-ray; 1.80 A; A/C=1-277.
DR PDB; 4EHN; X-ray; 1.69 A; A=1-277.
DR PDB; 4JJE; X-ray; 1.48 A; A=29-277.
DR PDB; 4JQY; X-ray; 2.50 A; A/B=34-277.
DR PDB; 4JQZ; X-ray; 2.89 A; A/B=34-277.
DR PDB; 4JR0; X-ray; 1.80 A; A/B=34-277.
DR PDBsum; 1CP3; -.
DR PDBsum; 1GFW; -.
DR PDBsum; 1I3O; -.
DR PDBsum; 1NME; -.
DR PDBsum; 1NMQ; -.
DR PDBsum; 1NMS; -.
DR PDBsum; 1PAU; -.
DR PDBsum; 1QX3; -.
DR PDBsum; 1RE1; -.
DR PDBsum; 1RHJ; -.
DR PDBsum; 1RHK; -.
DR PDBsum; 1RHM; -.
DR PDBsum; 1RHQ; -.
DR PDBsum; 1RHR; -.
DR PDBsum; 1RHU; -.
DR PDBsum; 2C1E; -.
DR PDBsum; 2C2K; -.
DR PDBsum; 2C2M; -.
DR PDBsum; 2C2O; -.
DR PDBsum; 2CDR; -.
DR PDBsum; 2CJX; -.
DR PDBsum; 2CJY; -.
DR PDBsum; 2CNK; -.
DR PDBsum; 2CNL; -.
DR PDBsum; 2CNN; -.
DR PDBsum; 2CNO; -.
DR PDBsum; 2DKO; -.
DR PDBsum; 2H5I; -.
DR PDBsum; 2H5J; -.
DR PDBsum; 2H65; -.
DR PDBsum; 2J30; -.
DR PDBsum; 2J31; -.
DR PDBsum; 2J32; -.
DR PDBsum; 2J33; -.
DR PDBsum; 2XYG; -.
DR PDBsum; 2XYH; -.
DR PDBsum; 2XYP; -.
DR PDBsum; 2XZD; -.
DR PDBsum; 2XZT; -.
DR PDBsum; 2Y0B; -.
DR PDBsum; 3DEH; -.
DR PDBsum; 3DEI; -.
DR PDBsum; 3DEJ; -.
DR PDBsum; 3DEK; -.
DR PDBsum; 3EDQ; -.
DR PDBsum; 3GJQ; -.
DR PDBsum; 3GJR; -.
DR PDBsum; 3GJS; -.
DR PDBsum; 3GJT; -.
DR PDBsum; 3H0E; -.
DR PDBsum; 3ITN; -.
DR PDBsum; 3KJF; -.
DR PDBsum; 3PCX; -.
DR PDBsum; 3PD0; -.
DR PDBsum; 3PD1; -.
DR PDBsum; 4DCJ; -.
DR PDBsum; 4DCO; -.
DR PDBsum; 4DCP; -.
DR PDBsum; 4EHA; -.
DR PDBsum; 4EHD; -.
DR PDBsum; 4EHF; -.
DR PDBsum; 4EHH; -.
DR PDBsum; 4EHK; -.
DR PDBsum; 4EHL; -.
DR PDBsum; 4EHN; -.
DR PDBsum; 4JJE; -.
DR PDBsum; 4JQY; -.
DR PDBsum; 4JQZ; -.
DR PDBsum; 4JR0; -.
DR ProteinModelPortal; P42574; -.
DR SMR; P42574; 29-277.
DR DIP; DIP-268N; -.
DR IntAct; P42574; 21.
DR MINT; MINT-147180; -.
DR STRING; 9606.ENSP00000311032; -.
DR BindingDB; P42574; -.
DR ChEMBL; CHEMBL2334; -.
DR DrugBank; DB01065; Melatonin.
DR DrugBank; DB01017; Minocycline.
DR DrugBank; DB00641; Simvastatin.
DR GuidetoPHARMACOLOGY; 1619; -.
DR MEROPS; C14.003; -.
DR PhosphoSite; P42574; -.
DR DMDM; 77416852; -.
DR OGP; P42574; -.
DR PaxDb; P42574; -.
DR PeptideAtlas; P42574; -.
DR PRIDE; P42574; -.
DR DNASU; 836; -.
DR Ensembl; ENST00000308394; ENSP00000311032; ENSG00000164305.
DR Ensembl; ENST00000523916; ENSP00000428929; ENSG00000164305.
DR GeneID; 836; -.
DR KEGG; hsa:836; -.
DR UCSC; uc003iwh.3; human.
DR CTD; 836; -.
DR GeneCards; GC04M185548; -.
DR HGNC; HGNC:1504; CASP3.
DR HPA; CAB000091; -.
DR HPA; CAB008381; -.
DR HPA; HPA002643; -.
DR MIM; 600636; gene.
DR neXtProt; NX_P42574; -.
DR PharmGKB; PA26087; -.
DR eggNOG; NOG279444; -.
DR HOGENOM; HOG000231878; -.
DR HOVERGEN; HBG050802; -.
DR InParanoid; P42574; -.
DR KO; K02187; -.
DR OMA; SSFVCVL; -.
DR OrthoDB; EOG7TTQ7K; -.
DR PhylomeDB; P42574; -.
DR BRENDA; 3.4.22.56; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_578; Apoptosis.
DR EvolutionaryTrace; P42574; -.
DR GeneWiki; Caspase_3; -.
DR GenomeRNAi; 836; -.
DR NextBio; 3478; -.
DR PMAP-CutDB; P42574; -.
DR PRO; PR:P42574; -.
DR ArrayExpress; P42574; -.
DR Bgee; P42574; -.
DR CleanEx; HS_CASP3; -.
DR Genevestigator; P42574; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; EXP:Reactome.
DR GO; GO:0004861; F:cyclin-dependent protein serine/threonine kinase inhibitor activity; IEA:Ensembl.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008635; P:activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c; TAS:Reactome.
DR GO; GO:0006309; P:apoptotic DNA fragmentation; TAS:Reactome.
DR GO; GO:0001782; P:B cell homeostasis; IEA:Ensembl.
DR GO; GO:0045165; P:cell fate commitment; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0035329; P:hippo signaling cascade; TAS:Reactome.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; IEA:Ensembl.
DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR GO; GO:0046007; P:negative regulation of activated T cell proliferation; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IGI:MGI.
DR GO; GO:0030889; P:negative regulation of B cell proliferation; IEA:Ensembl.
DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030264; P:nuclear fragmentation involved in apoptotic nuclear change; IMP:HGNC.
DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0016485; P:protein processing; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IEA:Ensembl.
DR GO; GO:0034612; P:response to tumor necrosis factor; TAS:BHF-UCL.
DR GO; GO:0009411; P:response to UV; IEA:Ensembl.
DR GO; GO:0009611; P:response to wounding; IEA:Ensembl.
DR GO; GO:0007605; P:sensory perception of sound; IEA:Ensembl.
DR GO; GO:0043029; P:T cell homeostasis; IEA:Ensembl.
DR InterPro; IPR011600; Pept_C14_caspase.
DR InterPro; IPR001309; Pept_C14_ICE_p20.
DR InterPro; IPR016129; Pept_C14_ICE_p20_AS.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR015917; Pept_C14A_p45_core.
DR Pfam; PF00656; Peptidase_C14; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00115; CASc; 1.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS01121; CASPASE_HIS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Apoptosis; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Hydrolase; Phosphoprotein; Polymorphism;
KW Protease; Reference proteome; S-nitrosylation; Thiol protease;
KW Zymogen.
FT PROPEP 1 9
FT /FTId=PRO_0000004569.
FT PROPEP 10 28
FT /FTId=PRO_0000004570.
FT CHAIN 29 175 Caspase-3 subunit p17.
FT /FTId=PRO_0000004571.
FT CHAIN 176 277 Caspase-3 subunit p12.
FT /FTId=PRO_0000004572.
FT ACT_SITE 121 121 By similarity.
FT ACT_SITE 163 163 By similarity.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 26 26 Phosphoserine (By similarity).
FT MOD_RES 163 163 S-nitrosocysteine; in inhibited form.
FT VARIANT 22 22 H -> R (in dbSNP:rs35578277).
FT /FTId=VAR_048616.
FT VARIANT 190 190 E -> D (in dbSNP:rs1049210).
FT /FTId=VAR_001401.
FT CONFLICT 31 36 ISLDNS -> MSWDTG (in Ref. 3; CAC88866).
FT STRAND 41 51
FT HELIX 57 59
FT HELIX 67 80
FT STRAND 84 90
FT HELIX 93 105
FT HELIX 108 110
FT STRAND 111 120
FT STRAND 126 129
FT STRAND 132 135
FT HELIX 136 141
FT TURN 145 147
FT HELIX 149 151
FT STRAND 156 162
FT STRAND 165 167
FT STRAND 178 181
FT TURN 183 185
FT TURN 189 192
FT STRAND 193 199
FT STRAND 206 208
FT TURN 209 211
FT HELIX 214 226
FT TURN 227 229
FT HELIX 232 246
FT HELIX 254 256
FT STRAND 264 267
FT STRAND 270 272
SQ SEQUENCE 277 AA; 31608 MW; 2F35CD3BCF7FF64A CRC64;
MENTENSVDS KSIKNLEPKI IHGSESMDSG ISLDNSYKMD YPEMGLCIII NNKNFHKSTG
MTSRSGTDVD AANLRETFRN LKYEVRNKND LTREEIVELM RDVSKEDHSK RSSFVCVLLS
HGEEGIIFGT NGPVDLKKIT NFFRGDRCRS LTGKPKLFII QACRGTELDC GIETDSGVDD
DMACHKIPVE ADFLYAYSTA PGYYSWRNSK DGSWFIQSLC AMLKQYADKL EFMHILTRVN
RKVATEFESF SFDATFHAKK QIPCIVSMLT KELYFYH
//

MIM 600636
*RECORD*
*FIELD* NO
600636
*FIELD* TI
*600636 CASPASE 3, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP3
;;PARP CLEAVAGE PROTEASE;;
read moreAPOPAIN;;
CPP32;;
YAMA
*FIELD* TX

DESCRIPTION

Cysteinyl aspartate-specific proteases, or caspases, such as CASP3,
cleave substrates directly after an aspartic acid residue and play
essential roles in programmed cell death. Caspases are synthesized in a
dormant form with an N-terminal prodomain followed by a large subunit
and a small subunit. Proteolytic processing releases the caspase large
and small subunits, resulting in activation (summary by Parker et al.,
2010).

CLONING

Fernandes-Alnemri et al. (1994) cloned a gene encoding a 277-amino acid,
32-kD putative cysteine protease that they designated CPP32 from human
Jurkat T cells. The CPP32 proenzyme undergoes proteolytic cleavage to
produce 2 subunits, termed p20 and p11, which dimerize to form the
active enzyme. CPP32 shares significant homology with mammalian ICE
(CASP1; 147678), mouse Nedd2 (CASP2; 600639), and the Caenorhabditis
elegans cell death protein Ced3. CPP32 showed highest expression in cell
lines of lymphocytic origin.

By seaching EST databases for sequences encoding the pentapeptide motif
QACRG, which encompasses the catalytic cysteine of ICE, followed by
screening an umbilical vein endothelial cell cDNA library, Tewari et al.
(1995) cloned CASP3, which they called Yama after the Hindu god of
death.

Huang et al. (2001) identified and cloned a short CASP3 splice variant,
which they called CASP3s, from a human carcinoma cell line. CASP3s
appeared to result from a deletion of exon 6 that shifts the reading
frame in the C terminus, leading to an altered amino acid sequence and a
truncated polypeptide. The deduced 182-amino acid protein contains the
complete N terminus but is missing 95 residues at the C terminus,
including the conserved QACRG sequence at the catalytic site. PCR
analysis of 16 human tissues revealed expression of full-length CASP3,
as well as CASP3s at somewhat lower levels, in all tissues tested.
Western blot analysis of 3 cell lines revealed the prominent CASP3 band
at 32 kD and CASP3s at 20 kD. Several human cancer cell lines showed
coexpression of both variants at the mRNA and protein levels.
Overexpression of the catalytically inactive CASP3s by human kidney
cells offered some resistance to inducers of apoptosis, and CASP3s
accumulation could be enhanced with addition of proteasome inhibitors.

GENE FUNCTION

Fernandes-Alnemri et al. (1994) found that overexpression of CPP32 in
insect cells induced apoptosis. Coexpression of the 2 CPP32 subunits in
insect cells also resulted in apoptosis.

An early event that occurs concomitantly with the onset of apoptosis is
the proteolytic breakdown of poly(ADP-ribose) polymerase (PARP; 173870)
by a protease with properties resembling those of caspase-1. The
resulting cleavage, between asp216 and gly217, separates the N-terminal
DNA-nick sensor of PARP from its C-terminal catalytic domain. To
identify the enzyme responsible for PARP inactivation in mammalian cells
during apoptosis, Nicholson et al. (1995) purified the activity to
homogeneity from cultured human cells of malignant cell lines with
relatively high levels of this proteolytic activity. This enzyme, which
they named apopain, was composed of 2 subunits of relative molecular
masses 17 and 12 kD derived from a common proenzyme identified as CPP32.
Nicholson et al. (1995) developed a potent peptide aldehyde inhibitor
and showed that it prevented apoptotic events in vitro, suggesting that
apopain/CPP32 is important for the initiation of apoptotic cell death.

Tewari et al. (1995) showed that purified human ICE cleaved the Yama
proenzyme into a proteolytically active form and that activated Yama
cleaved PARP into the 85-kD apoptotic form. They also found that
poxvirus crimA interacted directly with activated Yama, but not Yama
proenzyme, and inhibited Yama-dependent PARP activation.

Fernandes-Alnemri et al. (1996) showed that CPP32 could be cleaved from
its proenzyme form to its 2 subunits by either granzyme B (GZMB; 123910)
or by a related cysteine protease, MCH4 (601762).

Quan et al. (1996) independently showed that granzyme B proteolytically
activated human Yama.

Apoptosis of human endothelial cells after growth factor deprivation is
associated with rapid and dramatic upregulation of cyclin A-associated
cyclin-dependent kinase-2 (CDK2; 116953) activity. Levkau et al. (1998)
showed that in apoptotic cells the carboxyl termini of the CDK
inhibitors CDKN1A (116899) and CDKN1B (600778) are truncated by specific
cleavage. The enzyme involved in this cleavage is CASP3 and/or a
CASP3-like caspase. After cleavage, CDKN1A loses its nuclear
localization sequence and exits the nucleus. Cleavage of CDKN1A and
CDKN1B resulted in a substantial reduction in their association with
nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2
activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant
to caspase cleavage, partially suppressed apoptosis. These data
suggested that CDK2 activation, through caspase-mediated cleavage of CDK
inhibitors, may be instrumental in the execution of apoptosis following
caspase activation.

Mannick et al. (1999) demonstrated that caspase-3 zymogens are
S-nitrosylated on their catalytic-site cysteine in unstimulated human
cell lines and denitrosylated upon activation of the Fas (134637)
apoptotic pathway. Decreased caspase-3 S-nitrosylation was associated
with an increase in intracellular caspase activity. Fas therefore
activates caspase-3 not only by inducing the cleavage of the caspase
zymogen to its active subunits, but also by stimulating the
denitrosylation of its active-site thiol. Protein
S-nitrosylation/denitrosylation can thus serve as a regulatory process
in signal transduction pathways. Mannick et al. (1999) suggested that
nitric oxide-related activity helps maintain caspase-3 zymogen in an
inactive form and that this regulation is achieved by S-nitrosylation of
the catalytic-site cysteine.

Gervais et al. (1999) found that the amyloid-beta 4A precursor protein
(APP; 104760) is directly and efficiently cleaved by caspases during
apoptosis, resulting in elevated amyloid-beta peptide formation. The
predominant site of caspase-mediated proteolysis is within the
cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal
neurons in vivo following acute excitotoxic or ischemic brain injury.
Caspase-3 is the predominant caspase involved in APP cleavage,
consistent with its marked elevation in dying neurons of Alzheimer
disease (104300) brains and colocalization of its APP cleavage product
with amyloid-beta in senile plaques. Caspases thus appear to play a dual
role in proteolytic processing of APP and the resulting propensity for
amyloid-beta peptide formation, as well as in the ultimate apoptotic
death of neurons in Alzheimer disease.

Huntington disease (143100) is a neurodegenerative disorder caused by
trinucleotide repeat expansion mutations, which result in extended
polyglutamine tracts in the huntingtin protein (613004). Transgenic mice
expressing N-terminal mutant huntingtin show intranuclear huntingtin
accumulation and develop progressive neurologic symptoms. Inhibiting
caspase-1 (147678) can prolong the survival of these HD mice. Li et al.
(2000) reported that intranuclear huntingtin induces the activation of
caspase-3 and the release of cytochrome c (123970) from mitochondria in
cultured cells. As a result, cells expressing intranuclear huntingtin
underwent apoptosis. Intranuclear huntingtin increased the expression of
caspase-1, which may in turn activate caspase-3 and trigger apoptosis.
The authors proposed that the increased level of caspase-1 induced by
intranuclear huntingtin may contribute to HD-associated cell death.

The cellular alterations associated with skeletal muscle differentiation
share a high degree of similarity with key phenotypic changes usually
ascribed to apoptosis. For example, actin fiber
disassembly/reorganization is a conserved feature of both apoptosis and
differentiating myoblasts, and the conserved muscle contractile protein
myosin light chain kinase (MYLK; 600922) is required for the apoptotic
feature of membrane blebbing. As such, these observations suggest that
the induction of differentiation and apoptosis in the myogenic lineage
may use overlapping cellular mechanisms. Fernando et al. (2002) reported
that skeletal muscle differentiation depends on the activity of the key
apoptotic protease caspase-3. Peptide inhibition of caspase-3 activity
or homozygous deletion of caspase-3 leads to dramatic reduction in both
myotube/myofiber formation and expression of muscle-specific proteins.
Fernando et al. (2002) identified mammalian sterile 20-like kinase
(MST1; 604965) as a crucial caspase-3 effector in this cellular process.
MST1 is cleavage-activated by caspase-3, and restoration of this
truncated kinase in caspase-3-null myoblasts restores the
differentiation phenotype. Taken together, these results confirm a
unique and unanticipated role for a caspase-3-mediated signal cascade in
the promotion of myogenesis.

Phosphatidylserine (PS) is sequestered in the inner membrane leaflet
through the activity of aminophospholipid translocase (see 609542).
Phagocytosis of erythrocytes is largely dependent upon the presence of
PS on the outer membrane leaflet. Mandal et al. (2002) found that
pro-CASP3 was expressed in mature anucleated human erythrocytes. CASP3
was activated following oxidative stress, concomitant with PS
externalization and erythrocyte phagocytosis. Pharmacologic inhibition
of CASP3 partly blocked PS externalization and erythrocyte phagocytosis.
Mandal et al. (2002) concluded that activated CASP3 blocks PS
translocase activity, promoting loss of PS asymmetric distribution and
phagocytosis of erythrocytes.

Jiang et al. (2003) identified a small molecule,
alpha-(trichloromethyl)-4-pyridineethanol (PETCM), as an activator of
caspase-3 by stimulation of apoptosome formation.

Okuyama et al. (2004) found that pure keratinocytes cultured from
embryonic day-15.5 mouse embryos committed irreversibly to
differentiation much earlier than those cultured from newborn mice.
Notch signaling, which promotes keratinocyte differentiation, was
upregulated in embryonic keratinocytes and epidermis, and elevated
caspase-3 expression, which the authors identified as a target for
Notch1 (190198) transcriptional activation, accounted in part for the
high commitment of embryonic keratinocytes to terminal differentiation.

Chang et al. (2003) examined cardiac SRF (600589) protein levels from 23
patients with end-stage heart failure, 10 of whom were supported by left
ventricular assist devices (LVAD), and 7 normal hearts. Full-length SRF
was markedly reduced and processed into 55- and 32-kD subfragments in
the 13 unsupported failing hearts. SRF was intact in normal samples,
whereas samples from the hearts of the 10 LVAD patients showed minimal
SRF fragmentation. Specific antibodies to N- and C-terminal SRF
sequences and site-directed mutagenesis revealed 2 alternative caspase-3
cleavage sites. Expression of the 32-kD N-terminal SRF fragment in
myogenic cells inhibited the transcriptional activity of alpha-actin
(102610) gene promoters by 50 to 60%. Chang et al. (2003) concluded that
caspase-3 activation in heart failure sequentially cleaves SRF and
generates a truncated SRF that appears to function as a
dominant-negative transcription factor. They suggested that caspase-3
activation may be reversible in the failing heart with ventricular
unloading.

Miura et al. (2004) reported delayed ossification and decreased bone
mineral density of Casp3-deficient mice due to attenuated osteogenic
differentiation of bone marrow stromal cells. The mechanism for the
impaired differentiation involved overactivation of the transforming
growth factor beta-1 (TGFB1; 190180)/SMAD2 (601366) signaling pathway,
ultimately resulting in increased replicative senescence. CASP3
inhibitor caused accelerated bone loss in ovariectomized mice, a model
for postmenopausal osteoporosis. Miura et al. (2004) concluded that the
CASP3 influence on bone mineral density should be considered in any in
vivo application of CASP3 inhibitors to the treatment of human disease.

Ribeil et al. (2007) demonstrated that during erythroid differentiation
but not apoptosis, the chaperone protein Hsp70 (140550) protects GATA1
(305371) from caspase-mediated proteolysis. At the onset of caspase
activation, Hsp70 colocalizes and interacts with GATA1 in the nucleus of
erythroid precursors undergoing terminal differentiation. In contrast,
erythropoietin starvation induces the nuclear export of Hsp70 and the
cleavage of GATA1. In an in vitro assay, Hsp70 protected GATA1 from
CASP3-mediated proteolysis through its peptide-binding domain. Ribeil et
al. (2007) used RNA-mediated interference to decrease the Hsp70 content
of erythroid precursors cultured in the presence of erythropoietin. This
led to GATA1 cleavage, a decrease in hemoglobin content, downregulation
of the expression of the antiapoptotic protein Bcl-XL (see 600039), and
cell death by apoptosis. These effects were abrogated by the
transduction of a caspase-resistant GATA1 mutant. Thus, Ribeil et al.
(2007) concluded that in erythroid precursors undergoing terminal
differentiation, Hsp70 prevents active CASP3 from cleaving GATA1 and
inducing apoptosis.

Nitric oxide (see 163731) acts substantially in cellular signal
transduction through stimulus-coupled S-nitrosylation of cysteine
residues. Benhar et al. (2008) searched for denitrosylase activities,
and focused on caspase-3, an exemplar of stimulus-dependent
denitrosylation, and identified thioredoxin (see 187700) and thioredoxin
reductase (see 601112) in a biochemical screen. In resting human
lymphocytes, thioredoxin-1 actively denitrosylated cytosolic caspase-3
and thereby maintained a low steady-state amount of S-nitrosylation.
Upon stimulation of Fas, thioredoxin-2 (609063) mediated denitrosylation
of mitochondria-associated caspase-3, a process required for caspase-3
activation, and promoted apoptosis. Inhibition of
thioredoxin-thioredoxin reductases enabled identification of additional
substrates subject to endogenous S-nitrosylation. These substrates
included caspase-9 (CASP9; 602234) and protein tyrosine phosphatase-1B
(176885). Thus, Benhar et al. (2008) concluded that specific enzymatic
mechanisms may regulate basal and stimulus-induced denitrosylation in
mammalian cells.

Srikanth et al. (2010) found that during infection of intestinal
epithelial cells with the Salmonella serovar Typhimurium, the effector
Salmonella invasion protein A (SipA) is responsible for the early
activation of caspase-3, an enzyme that is required for SipA cleavage at
a specific recognition motif that divides the protein into its 2
functional domains and activates SipA in a manner necessary for
pathogenicity. Other caspase-3 cleavage sites identified in S.
Typhimurium appeared to be restricted to secreted effector proteins,
which indicated that this may be a general strategy used by this
pathogen for processing of its secreted effectors.

Using rat and mouse hippocampal brain slices, Li et al. (2010) showed
that the Casp9-Casp3 mitochondrial signaling pathway used to induce
apoptosis also has a role in neuronal plasticity. Activation of Casp3
was required for long-term synaptic depression and AMPA receptor (see
138248) internalization, but not for long-term potentiation. Long-term
depression and AMPA receptor internalization were blocked by peptide
inhibitors of Casp3 and Casp9. In hippocampal slices from Casp3 -/-
mice, long-term depression was abolished, whereas long-term potentiation
remained intact. Long-term depression was also abolished by
overexpression of the antiapoptotic proteins Xiap (300079) or Bclxl, and
by a mutant Atk1 (164730) protein that was resistant to Casp3
proteolysis. NMDA receptor (see 138249) stimulation that induced
long-term depression activated Casp3 in dendrites without causing cell
death. Li et al. (2010) concluded that CASP3 has a nonapoptotic role in
AMPA receptor internalization and synaptic plasticity.

Burguillos et al. (2011) showed that the orderly activation of caspase-8
(601763) and caspase-3/7 (601761), known executioners of apoptotic cell
death, regulate microglia activation through a protein kinase C-delta
(PRKCD; 176977)-dependent pathway. Burguillos et al. (2011) found that
stimulation of microglia with various inflammogens activates caspase-8
and caspase-3/7 in microglia without triggering cell death in vitro and
in vivo. Knockdown or chemical inhibition of each of these caspases
hindered microglia activation and consequently, reduced neurotoxicity.
The authors observed that these caspases are activated in microglia in
the ventral mesencephalon of Parkinson disease (168600) and the frontal
cortex of individuals with Alzheimer disease (104300). Burguillos et al.
(2011) concluded that caspase-8 and caspase-3/7 are involved in
regulating microglia activation, and suggested that inhibition of these
caspases could be neuroprotective by targeting the microglia rather than
the neurons themselves.

MAPPING

Nasir et al. (1997) used fluorescence in situ hybridization of a genomic
clone isolated from a P1 library to map CPP32 to the tip of the long arm
of human chromosome 4. Its localization was refined against a YAC contig
from this region spanning at least 2 Mb. CPP32 mapped between the KLKB1
(229000) and F11 (264900) loci on the one side and D4S254 on the other.
It was contained within the same 240-kb YAC as the FACL2 gene (152425).

Tiso et al. (1996) used radiation hybrid mapping to localize the CPP32
gene to human chromosome 4q33-q35.1. They observed that each of 4 CASP
family genes mapped colocalizes with an autosomal dominant malformative
disease. They suggested William syndrome (194050) as a candidate genetic
disease at the 4q33-q35 locus.

MOLECULAR GENETICS

Failure of apoptosis is one of the hallmarks of cancer. To explore the
possibility that genetic alterations in the CASP3 gene might be involved
in the development of human tumors, Soung et al. (2004) analyzed the
entire coding region and all splice sites of the gene for somatic
mutations in a series of 944 human tumors. Overall, they detected 14
somatic mutations: 4 of 98 colon carcinomas (4.1%), 4 of 181 nonsmall
cell lung cancers (2.2%), 2 of 129 non-Hodgkin lymphomas (1.6%), 2 of
165 stomach carcinomas (1.2%), 1 of 80 hepatocellular carcinomas (1.3%),
and 1 of 28 multiple myelomas (3.6%). No somatic mutations were found in
76 breast carcinomas, 45 acute leukemias, 12 medulloblastomas, 15 Wilms
tumors, 12 renal cell carcinomas, 40 esophagus carcinomas, 33 urinary
bladder carcinomas, and 33 laryngeal carcinomas.

- Associations Pending Confirmation

Kawasaki disease (KD; 611775) is an acute vasculitis syndrome which
predominantly affects small- and medium-sized arteries of infants and
children. Onouchi et al. (2010) reported that multiple variants in CASP3
that are in linkage disequilibrium conferred susceptibility to KD in
both Japanese and United States subjects of European ancestry. A G-to-A
substitution of a commonly associated SNP located in the 5-prime
untranslated region of CASP3 (dbSNP rs72689236) abolished binding of
nuclear factor of activated T cells (NFATC1; 600489) to the DNA sequence
surrounding the SNP. The authors suggested that altered CASP3 expression
in immune effector cells influences susceptibility to KD.

EVOLUTION

Human evolution is characterized by a dramatic increase in brain size
and complexity. To probe its genetic basis, Dorus et al. (2004) examined
the evolution of genes involved in diverse aspects of nervous system
biology. These genes, including CASP3, displayed significantly higher
rates of protein evolution in primates than in rodents. This trend was
most pronounced for the subset of genes implicated in nervous system
development. Moreover, within primates, the acceleration of protein
evolution was most prominent in the lineage leading from ancestral
primates to humans. Dorus et al. (2004) concluded that the phenotypic
evolution of the human nervous system has a salient molecular correlate,
i.e., accelerated evolution of the underlying genes, particularly those
linked to nervous system development.

ANIMAL MODEL

To analyze the function of CPP32 in vivo, Kuida et al. (1996) generated
CPP32-deficient mice by homologous recombination. These mice, born at a
frequency lower than expected by mendelian genetics, were smaller than
their littermates and died at 1 to 3 weeks of age. Although their
thymocytes retained normal susceptibility to various apoptotic stimuli,
brain development in CPP32-deficient mice was profoundly affected, and
discernible by embryonic day 12, resulting in a variety of hypoplasias
and disorganized cell deployment. These supernumerary cells were
postmitotic and terminally differentiated by the postnatal stage.
Pyknotic clusters at sites of major morphogenetic change during normal
brain development were not observed in the mutant embryos, indicating
increased apoptosis in the absence of CPP32. Thus, CPP32 was shown by
Kuida et al. (1996) to play a critical role during morphogenetic cell
death in the mammalian brain.

Woo et al. (1998) generated mice, embryonic stem (ES) cells, and mouse
embryonic fibroblasts (MEFs) lacking exon 3 of Casp3. The phenotype of
the mice was consistent with that observed by Kuida et al. (1996).
However, Woo et al. (1998) observed that in ES cells, Casp3 was
necessary for efficient apoptosis following ultraviolet but not gamma
irradiation. On the other hand, tumor necrosis factor (TNF; 191160)
induced normal apoptosis in Casp3 -/- thymocytes but defective apoptosis
in transformed MEFs. In addition, apoptotic events such as chromatin
condensation and DNA degradation were not displayed in all cell types;
however, other hallmarks of apoptosis were displayed by these cells. Woo
et al. (1998) concluded that the requirement for CASP3 in apoptosis is
tissue-specific and even stimulus-specific within the same cell type,
underscoring the complexity of apoptotic control in mammalian systems as
well as the potential for selective blocking of cell death.

Woo et al. (2003) reported that mice deficient in Casp3 had increased
numbers of splenic B cells showing both normal apoptosis and enhanced
proliferation in vivo and hyperproliferation after mitogenic stimulation
in vitro. However, in the absence of both Casp3 and Cdkn1a, the
hyperproliferation of Casp3 -/- B cells was abolished. Woo et al. (2003)
concluded that hyperproliferation of T cells in Casp3-deficient mice is
due to impaired apoptosis, whereas hyperproliferation in B cells is due
to increased cell cycling. The results indicated that Casp3 acts as a
negative regulator of cell cycle progression in B lymphocytes.

B-cell apoptosis has been implicated in the initiation of type-1
diabetes mellitus (IDDM; 222100) through antigen cross-presentation
mechanisms that lead to B cell-specific T-cell activation. Liadis et al.
(2005) found that Casp3 -/- mice were protected from developing diabetes
in a streptozotocin autoimmune diabetes model. Lymphocyte infiltration
of pancreatic islets was completely absent in Casp3 -/- mice. Further
studies showed that Casp3-mediated B-cell apoptosis was a requisite step
for T-cell priming and initiation of type 1 diabetes.

Zeiss et al. (2004) evaluated the impact of caspase-3 ablation on
photoreceptor degeneration and studied its role in postnatal retinal
development in the rd mouse. They found that Casp3-deficient mice
displayed marginal microphthalmia, peripapillary retinal dysplasia,
delayed regression of vitreal vasculature, and retarded apoptotic
kinetics of the inner nuclear layer. Although ablation of caspase-3
provided transient photoreceptor protection, rod death proceeded. Zeiss
et al. (2004) concluded that in vivo, caspase-3 is not critical for rod
photoreceptor development, nor does it play a significant role in
mediating pathologic rod death. The temporal nature of apoptotic
retardation in the absence of caspase-3 implied the presence of
caspase-independent mechanisms of developmental and pathologic cell
death.

Tao et al. (2005) had previously shown that the amount of Casp3 was
increased in a rat model of polycystic kidney disease (PKD; 173900).
They found that the caspase inhibitor IDN-8050 reduced kidney
enlargement by 44% and cyst volume by 29% in heterozygous (Cy/+) mutant
rats with PKD. In Cy/+ rats, caspase inhibition led to reduced blood
urea nitrogen and reduced numbers of Pcna (176740)-positive tubular
cells and apoptotic tubular cells. Western blot analysis showed that the
reduced amount of active Casp3 following IDN-8050 treatment was
associated with reduced cyst formation and disease progression.

Lakhani et al. (2006) generated mice doubly deficient for Casp3 and
Casp7, which died immediately after birth with defects in cardiac
development. Fibroblasts lacking both enzymes were highly resistant to
both mitochondrial and death receptor-mediated apoptosis, displayed
preservation of mitochondrial membrane potential, and had defective
nuclear translocation of apoptosis-inducing factor (AIF; 300169).
Furthermore, the early apoptotic events of Bax (600040) translocation
and cytochrome c (123970) release were also delayed. Lakhani et al.
(2006) concluded that caspases 3 and 7 are critical mediators of
mitochondrial events of apoptosis.

Using a clickbox test and auditory brainstem response analysis, Parker
et al. (2010) found that the 'melody' line of homozygous mutant mice,
which was generated in an N-ethyl-N-nitrosourea screen, exhibited
profound deafness. They identified the melody mutation as a
cys163-to-ser substitution in the catalytic site of Casp3. Scanning
electron microscopy and histologic analysis of homozygous melody mice
revealed disorganized sensory hair cells, hair cell loss, and
degeneration of spiral ganglion cells, with a gradient of severity from
apical to basal turns. Melody heterozygotes also showed evidence of loss
of spiral ganglion neurons, suggesting dominant-negative effects.

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*FIELD* CN
George E. Tiller - updated: 09/05/2013
Patricia A. Hartz - updated: 6/15/2012
Ada Hamosh - updated: 7/8/2011
Patricia A. Hartz - updated: 12/28/2010
Ada Hamosh - updated: 11/29/2010
Patricia A. Hartz - updated: 1/22/2009
Ada Hamosh - updated: 6/10/2008
Ada Hamosh - updated: 2/20/2007
Ada Hamosh - updated: 4/18/2006
Marla J. F. O'Neill - updated: 1/14/2005
Stylianos E. Antonarakis - updated: 1/10/2005
Marla J. F. O'Neill - updated: 10/22/2004
Jane Kelly - updated: 8/6/2004
Victor A. McKusick - updated: 7/14/2004
Patricia A. Hartz - updated: 5/12/2004
Paul J. Converse - updated: 9/24/2003
Ada Hamosh - updated: 2/6/2003
Victor A. McKusick - updated: 10/8/2002
Patricia A. Hartz - updated: 5/15/2002
Paul J. Converse - updated: 4/25/2002
George E. Tiller - updated: 2/5/2001
Stylianos E. Antonarakis - updated: 5/21/1999
Ada Hamosh - updated: 5/7/1999
Stylianos E. Antonarakis - updated: 1/21/1999
Alan F. Scott - updated: 4/2/1997
Victor A. McKusick - updated: 2/12/1997

*FIELD* CD
Victor A. McKusick: 7/5/1995

*FIELD* ED
alopez: 09/05/2013
mgross: 6/26/2012
terry: 6/15/2012
alopez: 7/12/2011
terry: 7/8/2011
mgross: 1/11/2011
terry: 12/28/2010
alopez: 12/1/2010
terry: 11/29/2010
terry: 5/20/2010
carol: 9/15/2009
mgross: 1/22/2009
terry: 1/22/2009
carol: 11/20/2008
alopez: 6/11/2008
terry: 6/10/2008
carol: 12/26/2007
alopez: 2/22/2007
terry: 2/20/2007
alopez: 4/24/2006
terry: 4/18/2006
carol: 1/18/2005
terry: 1/14/2005
mgross: 1/10/2005
carol: 11/18/2004
carol: 11/12/2004
carol: 10/22/2004
terry: 10/22/2004
tkritzer: 8/6/2004
tkritzer: 7/20/2004
terry: 7/14/2004
mgross: 5/13/2004
terry: 5/12/2004
alopez: 10/16/2003
mgross: 9/24/2003
alopez: 2/11/2003
terry: 2/6/2003
tkritzer: 10/17/2002
tkritzer: 10/8/2002
carol: 5/15/2002
mgross: 4/25/2002
cwells: 2/5/2001
cwells: 1/31/2001
mgross: 5/24/1999
mgross: 5/21/1999
alopez: 5/7/1999
terry: 5/7/1999
carol: 1/21/1999
alopez: 5/30/1997
alopez: 4/4/1997
alopez: 4/2/1997
terry: 2/12/1997
terry: 2/7/1997
mark: 1/6/1997
mark: 11/27/1996
terry: 11/25/1996
mark: 7/5/1995