Caspase 3: Difference between revisions

'''Caspase-3''' is a [[caspase]] protein that interacts with [[caspase-8]] and [[caspase-9]]. It is encoded by the ''CASP3'' gene. ''CASP3'' [[orthologs]] <ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: CASP3 coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000164305_CASP3.xml | access-date = 2009-12-20 | archive-url = https://web.archive.org/web/20160303190753/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000164305_CASP3.xml | archive-date = 2016-03-03 | url-status = dead }}</ref> have been identified in numerous [[mammal]]s for which complete genome data are available. Unique orthologs are also present in [[bird]]s, [[lizard]]s, [[lissamphibian]]s, and [[teleost]]s.

The '''CASP3''' [[protein]] is a member of the '''c'''ysteine-'''asp'''artic acid prote'''ase''' ([[caspase]]) family.<ref name="pmid8861900">{{cite journal | vauthors = Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J | title = Human ICE/CED-3 protease nomenclature | journal = Cell | volume = 87 | issue = 2 | pages = 171 | date = October 1996 | pmid = 8861900 | doi = 10.1016/S0092-8674(00)81334-3 | s2cid = 5345060 | doi-access = free }}</ref> Sequential activation of caspases plays a central role in the execution-phase of [[apoptosis|cell apoptosis]]. Caspases exist as inactive [[proenzyme]]s that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active [[enzyme]]. This protein cleaves and activates [[Caspase 6|caspases 6]] and [[Caspase 7|7]]; and the protein itself is processed and activated by caspases 8, 9, and [[Caspase 10|10]]. It is the predominant caspase involved in the cleavage of [[Early-onset Alzheimer's disease#APP .E2.80.93– Amyloidamyloid beta .28A4.29(A4) precursor protein|amyloid-beta 4A precursor protein]], which is associated with neuronal death in [[Alzheimer's disease]].<ref>{{cite journal | vauthors = Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW | title = Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation | journal = Cell | volume = 97 | issue = 3 | pages = 395–406 | date = April 1999 | pmid = 10319819 | doi=10.1016/s0092-8674(00)80748-5| s2cid = 17524567 | doi-access = free }}</ref> Alternative splicing of this gene results in two transcript variants that encode the same protein.<ref>{{cite web | title = Entrez Gene: CASP3 caspase 3, apoptosis-related cysteine peptidase| url = httphttps://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=836| accessdate = }}</ref>

|[[File:Extrinsic and intrinsic pathways to caspase-3 activation.jpg|thumb|300px|Pathways leading to caspase 3 activation.<ref name="pmid19077196">{{cite journal | vauthors = Harrington HA, Ho KL, Ghosh S, Tung KC | title = Construction and analysis of a modular model of caspase activation in apoptosis | journal = TheorTheoretical BiolBiology Med& ModelMedical Modelling | volume = 5 | issue = 1 | pages = 26 | year = 2008 | pmid = 19077196 | pmc = 2672941 | doi = 10.1186/1742-4682-5-26 | urldoi-access = | issn =free }}</ref>]]

Caspase-3 shares many of the typical characteristics common to all currently-known caspases. For example, its active site contains a [[cysteine]] residue (Cys-163) and [[histidine]] residue (His-121) that stabilize the [[peptide bond]] cleavage of a protein sequence to the carboxy-terminal side of an [[aspartic acid]] when it is part of a particular 4-amino acid sequence.<ref name="pmid9374030">{{cite journal | vauthors = Wyllie AH | title = Apoptosis: an overview | journal = Br.British Med.Medical Bull.Bulletin | volume = 53 | issue = 3 | pages = 451–65 | year = 1997 | pmid = 9374030 | doi = 10.1093/oxfordjournals.bmb.a011623| doi-access = free }}</ref><ref name="pmid9228015">{{cite journal | vauthors = Perry DK, Smyth MJ, Stennicke HR, Salvesen GS, Duriez P, Poirier GG, Hannun YA | title = Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 272 | issue = 30 | pages = 18530–3 | date = July 1997 | pmid = 9228015 | doi = 10.1074/jbc.272.30.18530 | doi-access = free }}</ref> This specificity allows caspases to be incredibly selective, with a 20,000-fold preference for aspartic acid over [[glutamic acid]].<ref name="pmid10947972">{{cite journal | vauthors = Stennicke HR, Renatus M, Meldal M, Salvesen GS | title = Internally quenched fluorescent peptide substrates disclose the subsite preferences of human caspases 1, 3, 6, 7 and 8 | journal = Biochem.The J.Biochemical Journal | volume = 350 | issue = 2 | pages = 563–8 | date = September 2000 | pmid = 10947972 | pmc = 1221285 | doi = 10.1042/0264-6021:3500563 }}</ref> A key feature of caspases in the cell is that they are present as [[zymogens]], termed procaspases, which are inactive until a biochemical change causes their activation. Each procaspase has an N-terminal large subunit of about 20 kDa followed by a smaller subunit of about 10 kDa, called p20 and p10, respectively.<ref name="pmid11803369">{{cite journal | vauthors = Salvesen GS | title = Caspases: opening the boxes and interpreting the arrows | journal = Cell Death Differ.and Differentiation | volume = 9 | issue = 1 | pages = 3–5 | date = January 2002 | pmid = 11803369 | doi = 10.1038/sj.cdd.4400963 | s2cid = 31274387 }}</ref>

Under normal circumstances, caspases recognize tetra-peptide sequences on their [[Substrate (biochemistry)|substrates]] and [[hydrolysis|hydrolyze]] peptide bonds after [[aspartic acid]] residues. Caspase 3 and [[caspase 7]] share similar substrate specificity by recognizing tetra-peptide motif Asp-x-x-Asp.<ref name="pmid17697120">{{cite journal | vauthors = Agniswamy J, Fang B, Weber IT | title = Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis | journal = The FEBS J.Journal | volume = 274 | issue = 18 | pages = 4752–65 | date = September 2007 | pmid = 17697120 | doi = 10.1111/j.1742-4658.2007.05994.x | s2cid = 1860924 }}</ref> The C-terminal Asp is absolutely required while variations at other three positions can be tolerated.<ref name="pmid16781734">{{cite journal | vauthors = Fang B, Boross PI, Tozser J, Weber IT | title = Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition | journal = J.Journal Mol.of Biol.Molecular Biology | volume = 360 | issue = 3 | pages = 654–66 | date = July 2006 | pmid = 16781734 | doi = 10.1016/j.jmb.2006.05.041 }}</ref> Caspase substrate specificity has been widely used in caspase based [[Enzyme inhibitor|inhibitor]] and drug design.<ref name="pmid18855730">{{cite journal | vauthors = Weber IT, Fang B, Agniswamy J | title = Caspases: structure-guided design of drugs to control cell death | journal = Mini RevReviews in MedMedicinal ChemChemistry | volume = 8 | issue = 11 | pages = 1154–62 | date = October 2008 | pmid = 18855730 | doi = 10.2174/138955708785909899 }}</ref>

Caspase-3, in particular, (also known as CPP32/Yama/apopain)<ref name="pmid7983002">{{cite journal | vauthors = Fernandes-Alnemri T, Litwack G, Alnemri ES | title = CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 269 | issue = 49 | pages = 30761–4 | date = December 1994 | doi = 10.1016/S0021-9258(18)47344-9 | pmid = 7983002 | doi-access = free }}</ref><ref name="pmid7774019">{{cite journal | vauthors = Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM | title = Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase | journal = Cell | volume = 81 | issue = 5 | pages = 801–9 | date = June 1995 | pmid = 7774019 | doi = 10.1016/0092-8674(95)90541-3 | s2cid = 18866447 | doi-access = free }}</ref><ref name="pmid7596430">{{cite journal | vauthors = Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA | title = Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis | journal = Nature | volume = 376 | issue = 6535 | pages = 37–43 | date = July 1995 | pmid = 7596430 | doi = 10.1038/376037a0 | bibcode = 1995Natur.376...37N | s2cid = 4240789 }}</ref> is formed from a 32 kDa zymogen that is cleaved into 17 kDa and 12 kDa subunits. When the procaspase is cleaved at a particular residue, the active heterotetramer can then be formed by hydrophobic interactions, causing four anti-parallel beta-sheets from p17 and two from p12 to come together to make a heterodimer, which in turn interacts with another heterodimer to form the full 12-stranded [[beta-sheet]] structure surrounded by [[alpha-helices]] that is unique to caspases.<ref name="pmid11803369"/><ref name="pmid16200200">{{cite journal | vauthors = Lavrik IN, Golks A, Krammer PH | title = Caspases: pharmacological manipulation of cell death | journal = J.The Clin.Journal Invest.of Clinical Investigation | volume = 115 | issue = 10 | pages = 2665–72 | date = October 2005 | pmid = 16200200 | pmc = 1236692 | doi = 10.1172/JCI26252 }}</ref> When the heterodimers align head-to-tail with each other, an active site is positioned at each end of the molecule formed by residues from both participating subunits, though the necessary Cys-285163 and His-237121 residues are found on the p17 (larger) subunit.<ref name="pmid16200200"/>

The catalytic site of caspase-3 involves the sulfohydrylthiol group of Cys-285163 and the [[imidazole]] ring of His-237121. His-237121 stabilizes the [[carbonyl]] group of the key aspartate residue, while Cys-285163 attacks to ultimately cleave the peptide bond. Cys-285163 and Gly-238 also function to stabilize the tetrahedral [[transition state]] of the substrate-enzyme complex through [[hydrogen bonding]].<ref name="pmid16200200"/> [[In vitro]], caspase-3 has been found to prefer the peptide sequence DEVDG (Asp-Glu-Val-Asp-Gly) with cleavage occurring on the carboxy side of the second aspartic acid residue (between D and G).<ref name="pmid10947972" /><ref name="pmid16200200"/><ref name="pmid10200555">{{cite journal | vauthors = Porter AG, Jänicke RU | title = Emerging roles of caspase-3 in apoptosis | journal = [[Cell Death Differ.]]and Differentiation | volume = 6 | issue = 2 | pages = 99–104 | date = February 1999 | pmid = 10200555 | doi = 10.1038/sj.cdd.4400476 | doi-access = free }}</ref> Caspase-3 is active over a broad [[pH]] range that is slightly higher (more basic) than many of the other executioner caspases. This broad range indicates that caspase-3 will be fully active under normal and apoptotic cell conditions.<ref name="pmid9325297">{{cite journal | vauthors = Stennicke HR, Salvesen GS | title = Biochemical characteristics of caspases-3, -6, -7, and -8 | journal = [[J.The Biol.Journal Chem.]]of Biological Chemistry | volume = 272 | issue = 41 | pages = 25719–23 | date = October 1997 | pmid = 9325297 | doi = 10.1074/jbc.272.41.25719 | doi-access = free }}</ref>

Caspase-3 is activated in the apoptotic cell both by extrinsic (death ligand) and intrinsic (mitochondrial) pathways.<ref name="pmid11803369"/><ref name="pmid19505876">{{cite journal | vauthors = Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, [[Andrew Halayko|Halayko AJ]], Los M | title = Apoptosis and cancer: mutations within caspase genes | journal = [[J.Journal Med.of Genet.]]Medical Genetics | volume = 46 | issue = 8 | pages = 497–510 | date = August 2009 | pmid = 19505876 | doi = 10.1136/jmg.2009.066944 | doi-access = free }}</ref> The zymogen feature of caspase-3 is necessary because if unregulated, caspase activity would kill cells indiscriminately.<ref name="pmid14644197">{{cite journal | vauthors = Boatright KM, Salvesen GS | title = Mechanisms of caspase activation | journal = [[Curr.Current Opin.Opinion in Cell Biol.]]Biology | volume = 15 | issue = 6 | pages = 725–31 | date = December 2003 | pmid = 14644197 | doi = 10.1016/j.ceb.2003.10.009 }}</ref> As an executioner caspase, the caspase-3 zymogen has virtually no activity until it is cleaved by an initiator caspase after apoptotic signaling events have occurred.<ref name="pmid19788411">{{cite journal | vauthors = Walters J, Pop C, Scott FL, Drag M, Swartz P, Mattos C, Salvesen GS, Clark AC | title = A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis | journal = [[Biochem.The J.]]Biochemical Journal | volume = 424 | issue = 3 | pages = 335–45 | date = December 2009 | pmid = 19788411 | pmc = 2805924 | doi = 10.1042/BJ20090825 }}</ref> One such signaling event is the introduction of [[granzyme B]], which can activate initiator caspases, into cells targeted for apoptosis by killer [[T cells]].<ref name="pmid11561209">{{cite journal | vauthors = Gallaher BW, Hille R, Raile K, Kiess W | title = Apoptosis: live or die--hard work either way! | journal = [[Horm.Hormone Metab.and Res.]]Metabolic Research | volume = 33 | issue = 9 | pages = 511–9 | date = September 2001 | pmid = 11561209 | doi = 10.1055/s-2001-17213 | urls2cid = http://www.thieme-connect.com/DOI/DOI?10.1055/s-2001-1721336623826 }}</ref><ref name="pmid11384748">{{cite journal | vauthors = Katunuma N, Matsui A, Le QT, Utsumi K, Salvesen G, Ohashi A | title = Novel procaspase-3 activating cascade mediated by lysoapoptases and its biological significances in apoptosis | journal = [[Adv.Advances in Enzyme Regul.]]Regulation | volume = 41 | issue = 1 | pages = 237–50 | year = 2001 | pmid = 11384748 | doi = 10.1016/S0065-2571(00)00018-2 }}</ref> This extrinsic activation then triggers the hallmark caspase cascade characteristic of the apoptotic pathway, in which caspase-3 plays a dominant role.<ref name="pmid9228015"/> In intrinsic activation, [[cytochrome c]] from the [[mitochondria]] works in combination with [[caspase-9]], apoptosis-activating factor 1 ([[Apaf-1]]), and [[Adenosine triphosphate|ATP]] to process procaspase-3.<ref name="pmid10200555" /><ref name="pmid11384748" /><ref name="pmid15055583">{{cite journal | vauthors = Li P, Nijhawan D, Wang X | title = Mitochondrial activation of apoptosis | journal = [[Cell (journal)|Cell]] | volume = 116 | issue = 2 Suppl | pages = S57–9, 2 p following S59 | date = January 2004 | pmid = 15055583 | doi = 10.1016/S0092-8674(04)00031-5 | s2cid = 5180966 | doi-access = free }}</ref> These molecules are sufficient to activate caspase-3 in vitro, but other regulatory proteins are necessary [[in vivo]].<ref name="pmid15055583" />

Mangosteen (''Garcinia Mangostanamangostana'') extract has been shown to inhibit the activation of caspase 3 in B-amyloid treated human neuronal cells.<ref name="pmid20232907">{{cite journal | vauthors = Moongkarndi P, Srisawat C, Saetun P, Jantaravinid J, Peerapittayamongkol C, Soi-ampornkul R, Junnu S, Sinchaikul S, Chen ST, Charoensilp P, Thongboonkerd V, Neungton N | title = Protective effect of mangosteen extract against beta-amyloid-induced cytotoxicity, oxidative stress and altered proteome in SK-N-SH cells | journal = J.Journal of Proteome Res.Research | volume = 9 | issue = 5 | pages = 2076–86 | date = May 2010 | pmid = 20232907 | doi = 10.1021/pr100049v | url = http://ntur.lib.ntu.edu.tw/bitstream/246246/243509/-1/134.pdf }}</ref>

One means of caspase inhibition is through the IAP (inhibitor of apoptosis) protein family, which includes c-IAP1, c-IAP2, [[XIAP]], and ML-IAP.<ref name="pmid16200200"/> XIAP binds and inhibits initiator caspase-9, which is directly involved in the activation of executioner caspase-3.<ref name="pmid15055583"/> During the caspase cascade, however, caspase-3 functions to inhibit XIAP activity by cleaving caspase-9 at a specific site, preventing XIAP from being able to bind to inhibit caspase-9 activity.<ref name="pmid17437405">{{cite journal | vauthors = Denault JB, Eckelman BP, Shin H, Pop C, Salvesen GS | title = Caspase 3 attenuates XIAP (X-linked inhibitor of apoptosis protein)-mediated inhibition of caspase 9 | journal = [[Biochem.The J.]]Biochemical Journal | volume = 405 | issue = 1 | pages = 11–9 | date = July 2007 | pmid = 17437405 | pmc = 1925235 | doi = 10.1042/BJ20070288 }}</ref>

* [[Caspase 8|CASP8]] <ref name="pmid11832478">{{cite journal | vauthors = Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES | title = Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 277 | issue = 16 | pages = 13430–7 | date = April 2002 | pmid = 11832478 | doi = 10.1074/jbc.M108029200 | doi-access = free }}</ref><ref name="pmid8962078">{{cite journal | vauthors = Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES | title = Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 93 | issue = 25 | pages = 14486–91 | date = December 1996 | pmid = 8962078 | pmc = 26159 | doi = 10.1073/pnas.93.25.14486 | bibcode = 1996PNAS...9314486S | doi-access = free }}</ref>

* [[NMT2]] <ref>{{Cite journal | last1 = Selvakumar | first1 = P. | last2 = Sharma | first2 = RK. | title = Role of calpain and caspase system in the regulation of N-myristoyltransferase in human colon cancer (Review). | journal = Int J Mol Med | volume = 19 | issue = 5 | pages = 823–7 |date=May 2007 | doi = 10.3892/ijmm.19.5.823| PMIDpmid = 17390089 | doi-access = free }}</ref>

* [[CFLAR]] <ref name="pmid9208847">{{cite journal | vauthors = Shu HB, Halpin DR, Goeddel DV | title = Casper is a FADD- and caspase-related inducer of apoptosis | journal = Immunity | volume = 6 | issue = 6 | pages = 751–63 | date = June 1997 | pmid = 9208847 | doi = 10.1016/S1074-7613(00)80450-1 | doi-access = free }}</ref><ref name="pmid9326610">{{cite journal | vauthors = Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, Baskin DG, Schwartz SM, Hood L | title = MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 94 | issue = 21 | pages = 11333–8 | date = October 1997 | pmid = 9326610 | pmc = 23459 | doi = 10.1073/pnas.94.21.11333 | bibcode = 1997PNAS...9411333H | doi-access = free }}</ref>

* [[Deleted in Colorectal Cancer|DCC]] <ref name="pmid11248093">{{cite journal | vauthors = Forcet C, Ye X, Granger L, Corset V, Shin H, Bredesen DE, Mehlen P | title = The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages = 3416–21 | date = March 2001 | pmid = 11248093 | pmc = 30668 | doi = 10.1073/pnas.051378298 | bibcode = 2001PNAS...98.3416F | doi-access = free }}</ref>

* [[GroEL]] <ref name="pmid10205158">{{cite journal | vauthors = Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S | title = Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells | journal = The EMBO J.Journal | volume = 18 | issue = 8 | pages = 2040–8 | date = April 1999 | pmid = 10205158 | pmc = 1171288 | doi = 10.1093/emboj/18.8.2040 }}</ref><ref name="pmid10205159">{{cite journal | vauthors = Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, Tawa P, Ruel R, Rosen A, Nicholson DW | title = Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis | journal = The EMBO J.Journal | volume = 18 | issue = 8 | pages = 2049–56 | date = April 1999 | pmid = 10205159 | pmc = 1171289 | doi = 10.1093/emboj/18.8.2049 }}</ref>

* [[HCLS1]] <ref name="pmid11988074">{{cite journal | vauthors = Ruzzene M, Penzo D, Pinna LA | title = Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells | journal = Biochem.The J.Biochemical Journal | volume = 364 | issue = Pt 1 | pages = 41–7 | date = May 2002 | pmid = 11988074 | pmc = 1222543 | doi = 10.1042/bj3640041}}</ref><ref name="pmid11689006">{{cite journal | vauthors = Chen YR, Kori R, John B, Tan TH | title = Caspase-mediated cleavage of actin-binding and SH3-domain-containing proteins cortactin, HS1, and HIP-55 during apoptosis | journal = Biochem.Biochemical Biophys.and Res.Biophysical Commun.Research Communications | volume = 288 | issue = 4 | pages = 981–9 | date = November 2001 | pmid = 11689006 | doi = 10.1006/bbrc.2001.5862 }}</ref>

* [[Survivin]] <ref name="pmid9850056">{{cite journal | vauthors = Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC | title = IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs | journal = Cancer Res.Research | volume = 58 | issue = 23 | pages = 5315–20 | date = December 1998 | pmid = 9850056 | doi = }}</ref><ref name="pmid11170436">{{cite journal | vauthors = Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH | title = An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7 | journal = Biochemistry | volume = 40 | issue = 4 | pages = 1117–23 | date = January 2001 | pmid = 11170436 | doi = 10.1021/bi001603q }}</ref>

* [[TRAF3]] <ref name="pmid11261798">{{cite journal | vauthors = Lee ZH, Lee SE, Kwack K, Yeo W, Lee TH, Bae SS, Suh PG, Kim HH | title = Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells | journal = J.Journal Leukoc.of Biol.Leukocyte Biology | volume = 69 | issue = 3 | pages = 490–6 | date = March 2001 | doi = 10.1189/jlb.69.3.490 | pmid = 11261798 | dois2cid = 34256107 }}</ref><ref name="pmid11098060">{{cite journal | vauthors = Leo E, Deveraux QL, Buchholtz C, Welsh K, Matsuzawa S, Stennicke HR, Salvesen GS, Reed JC | title = TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 276 | issue = 11 | pages = 8087–93 | date = March 2001 | pmid = 11098060 | doi = 10.1074/jbc.M009450200 | doi-access = free }}</ref>

* [[XIAP]] <ref name="pmid11447297">{{cite journal | vauthors = Suzuki Y, Nakabayashi Y, Takahashi R | title = Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 98 | issue = 15 | pages = 8662–7 | date = July 2001 | pmid = 11447297 | pmc = 37492 | doi = 10.1073/pnas.161506698 | bibcode = 2001PNAS...98.8662S | doi-access = free }}</ref><ref name="pmid11927604">{{cite journal | vauthors = Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL | title = The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites | journal = J.The Journal of Cell Biol.Biology | volume = 157 | issue = 1 | pages = 115–24 | date = April 2002 | pmid = 11927604 | pmc = 2173256 | doi = 10.1083/jcb.200108085 }}</ref><ref name="pmid11257232">{{cite journal | vauthors = Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS | title = Structural basis for the inhibition of caspase-3 by XIAP | journal = Cell | volume = 104 | issue = 5 | pages = 791–800 | date = March 2001 | pmid = 11257232 | doi = 10.1016/S0092-8674(01)00274-4 | s2cid = 17915093 | doi-access = free }}</ref><ref name="pmid9384571">{{cite journal | vauthors = Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC | title = The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases | journal = The EMBO J.Journal | volume = 16 | issue = 23 | pages = 6914–25 | date = December 1997 | pmid = 9384571 | pmc = 1170295 | doi = 10.1093/emboj/16.23.6914 }}</ref><ref name="pmid9230442">{{cite journal | vauthors = Deveraux QL, Takahashi R, Salvesen GS, Reed JC | title = X-linked IAP is a direct inhibitor of cell-death proteases | journal = Nature | volume = 388 | issue = 6639 | pages = 300–4 | date = July 1997 | pmid = 9230442 | doi = 10.1038/40901 | bibcode = 1997Natur.388..300D | s2cid = 4395885 | doi-access = free }}</ref><ref name="pmid11359776">{{cite journal | vauthors = Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R | title = X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 276 | issue = 29 | pages = 27058–63 | date = July 2001 | pmid = 11359776 | doi = 10.1074/jbc.M102415200 | doi-access = free}}</ref>

* [[NFE2L2]] <ref name="pmid10510468">{{cite journal | vauthors = Ohtsubo T, Kamada S, Mikami T, Murakami H, Tsujimoto Y | title = Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases. | journal = Cell Death Differ.and Differentiation | volume = 6 | issue = 9 | pages = 865–872865–72 | yeardate = September 1999 | pmid = 10510468 | doi = 10.1038/sj.cdd.4400566 | doi-access = free }}</ref>{{Divdiv col end}}

Caspase-3 has been found to be necessary for normal [[brain]] development as well as its typical role in apoptosis, where it is responsible for [[chromatin]] condensation and [[DNA]] fragmentation.<ref name="pmid10200555"/> Elevated levels of a fragment of Caspase-3, p17, in the bloodstream is a sign of a recent [[myocardial infarction]].<ref name="pmid21211695">{{cite journal | vauthors = Agosto M, Azrin M, Singh K, Jaffe AS, Liang BT | title = Serum caspase-3 p17 fragment is elevated in patients with ST-segment elevation myocardial infarction: a novel observation | journal = J.Journal Am.of Coll.the Cardiol.American College of Cardiology | volume = 57 | issue = 2 | pages = 220–1 | date = January 2011 | pmid = 21211695 | doi = 10.1016/j.jacc.2010.08.628 | doi-access = free }}</ref> It is now being shown that caspase-3 may play a role in embryonic and hematopoietic [[stem cell]] differentiation.<ref name="pmid18522841">{{cite journal | vauthors = Abdul-Ghani M, Megeney LA | title = Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation | journal = Cell Stem Cell | volume = 2 | issue = 6 | pages = 515–6 | date = June 2008 | pmid = 18522841 | doi = 10.1016/j.stem.2008.05.013 | doi-access = free }}</ref>

* {{cite journal | vauthors = Cohen GM | title = Caspases: the executioners of apoptosis. | journal = Biochem.The J.Biochemical Journal | volume = 326 | issue = Pt 1 | pages = 1–16 | yeardate = August 1997 | pmid = 9337844 | pmc = 1218630 | doi = | url = http://www10.biochemj.org1042/bj/326/0001/3260001.pdf bj3260001}}

* {{cite journalbook | vauthors = Roig J, Traugh JA | title = Cytostatic p21 G protein-activated protein kinase gamma-PAK. | journal = Vitam. Horm. | volume = 62 | issue = | pages = 167–98 | year = 2001 | pmid = 11345898 | doi = 10.1016/S0083-6729(01)62004-1 | series = Vitamins & Hormones | isbn = 9780127098623 }}

* {{cite journal | vauthors = Zhao LJ, Zhu H | title = Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design. | journal = Curr.Current Drug Targets. Immune, Endocr.Endocrine Metabol.and Disord.Metabolic Disorders | volume = 4 | issue = 4 | pages = 265–75 | yeardate = 2005December 2004 | pmid = 15578977 | doi = 10.2174/1568008043339668 }}

* {{cite journal | vauthors = Le Rouzic E, Benichou S | title = The Vpr protein from HIV-1: distinct roles along the viral life cycle. | journal = Retrovirology | volume = 2 | issue = 1 | pages = 11 | year = 2006 | pmid = 15725353 | pmc = 554975 | doi = 10.1186/1742-4690-2-11 | doi-access = free }}

* {{cite journal | vauthors = Sykes MC, Mowbray AL, Jo H | title = Reversible glutathiolation of caspase-3 by glutaredoxin as a novel redox signaling mechanism in tumor necrosis factor-alpha-induced cell death. | journal = Circ.Circulation Res.Research | volume = 100 | issue = 2 | pages = 152–4 | yeardate = February 2007 | pmid = 17272816 | doi = 10.1161/01.RES.0000258171.08020.72 | s2cid = 12684325 | doi-access = }}

* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/pepsum?id=C14.003 C14.003] {{Webarchive|url=https://web.archive.org/web/20160303211411/http://merops.sanger.ac.uk/cgi-bin/pepsum?id=C14.003 |date=2016-03-03 }}

* [httphttps://www.youtube.com/watch?v=l4D0YxGi5Ec Apoptosis & Caspase 3] -– [[The Proteolysis Map]]-animation

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