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FLASH GENE

Symbol

CASP3

contributors: mct/ - updated : 25-11-2015

HGNC name	caspase 3, apoptosis-related cysteine peptidase
HGNC id	1504

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	4q35.1      Physical location : 185.548.851 - 185.570.629
Synonym name	caspase 3, apoptosis-related cysteine protease
	Yama protein
	apopain
	procaspase 3
	PARP cleavage protease
	cysteine protease CPP32
	SREBP cleavage activity 1
Synonym symbol(s)	CPP32, SCA-1, CPP32B, Yama, apopain
EC.number	3.4.22.56

DNA

TYPE	functioning gene
STRUCTURE	21.78 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D4S1596 - CASP3 - D14S1552 - D4S2349 ,D4S1584 - D4S254 - D4S187 ,D4S130 - D4S163 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004346 8 splicing 2689 NP_004337 31.5 277 - 2013 23727203 variant alpha encoding the same protein than variant beta NM_032991 7 splicing 2522 NP_116786 31.5 277 - 2013 23727203 variant beta lacking 167nt in the 5' UTR compared to variant alpha encoding the same protein than variant alpha variant 3 - splicing - isoform 3 - 182 ubiquitous 2013 23727203 attenuate apoptosis induced by proteasome inhibition

EXPRESSION

Type

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive esophagus       highly   liver       highly Hearing/Equilibrium ear inner cochlea   highly Lymphoid/Immune lymph node       highly   spleen       highly Nervous brain       moderately Reproductive male system testis     lowly Respiratory lung       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid         Muscular striatum skeletal   moderately

cells

System Cell Pubmed Species Stage Rna symbol not specific mast cell Homo sapiens

cell lineage
cell lines	highly in cells of the immune system
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a short prodomain
	a N terminal (Fas-associating protein with DEATH domain) FADD-like death effector domain and
	a conserved QACXG pentapeptide active site motif

conjugated

PhosphoP

mono polymer

heteromer , tetramer

isoforms

Precursor

precursor producing two subunits, large (17kDa) and small (12kDa) that dimerize

HOMOLOGY

interspecies	homolog to rattus Casp3 (89.17 pc)
	homolog to murine Casp3 (86.64 pc)

Homologene

FAMILY	caspase family of cysteinyl-aspartate specific proteases
	caspase 3 subfamily
	peptidase C14A family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,inner
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
text	procaspase 3 stored in the mitochondrial intermembrane space and released into cytosol after appropriate apoptotic stimuli
	active caspase-3 can be stored within secretory compartments of viable mast cells
	in viable cells, is found as a cytosolic inactive proenzyme and CASP3 activation is largely confined to processes associated with cell death (pMID: 23817418)

basic FUNCTION	effector caspase in the Fas (TNFRSF6) proapoptotic pathway
	cleaving and activating CASP6, CASP7, CASP9
	involved in the activation cascade of caspases responsible for apoptosis execution
	involved in DNA repair and metabolism of PARP, SREBPs (huntingtin, APP and others)
	attenuates XIAP (X-linked inhibitor of apoptosis protein)-mediated inhibition of caspase 9
	predominant caspase involved in the cleavage of amyloid-beta 4A precursor
	primary effector that executes programmed cell death, and plays an important role in the development and progression of cancer
	CASP3 was found to be generally more promiscuous than CASP7 and appears to be the major executioner caspase during the demolition phase of apoptosis
	CASP3 and CASP7 are considered functionally redundant proteases with similar proteolytic specificities
	CASP3 and CASP7 exhibit differences in protease activity, specific homodimer-forming activity, and three-dimensional structural features, all of which are closely interrelated
	with SLC30A4, MAP1LC3A and CASP3 might play a role in the pathophysiology of recurrent neonatal seizure-induced acute and long-term brain damage
	key mediator of neuronal programmed cell death
	CASP3 activation, a crucial event of neuronal cell death program, is also a feature of many chronic neurodegenerative diseases
	protects stressed organs against cell death
	active CASP3 is removed from cells by release of CASP3-enriched vesicles
	involved in the signalling in erythroid differentiation by targeting late progenitors
	is a main executioner of apoptotic cell death
	key mediator of neuronal death in the acute stage of stroke
	CASP3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting CASP3 for treatment of stroke
	BIRC7, CASP3, BIRC5 are closely related to the occurrence and development of prostatic cancer
	in addition to their role in amyloid processing, CASP8 and its downstream effector CASP3 are involved in synaptic plasticity, learning, memory and control of microglia pro-inflammatory activation and associated neurotoxicity

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	N terminus of the membrane bound form and the cytoplasmic form are different
	heterotetramer consisting of two heterodimers of p12 and p17 cleaved for the preprotein form

INTERACTION

DNA

RNA

small molecule

protein	cleaving abundant cytoplasmic (i.e gelsolin, fodrin..) and nuclear (lamin, U1 SnRNP-70Kd) proteins kinases
	binding to and ubiquitinated by BIRC2
	interacting with DSG2 (apoptotic processing of DSG2 is mediated by caspase 3 in epithelial cells)
	presynaptic protein ATCAY is a substrate of CASP3 and CASP7
	PAWR is a novel substrate of CASP3 during apoptosis (the novel specific CASP3 cleavage site in PAWR, and the cleaved fragment of PAWR retains proapoptotic activity)
	ANP32B is a direct substrate for CASP3 and acted as a negative regulator for leukemic cell apoptosis
	TRIB3 might prevent cytoplasmic activation of CASP3 by promoting proCASP3 entry into the nucleus, and thereby inhibit apoptosis
	NUMBL could decrease the expression of TRAF6, CCND1, and MMP9 and increase the expression of CASP3
	NEK5,is a novel substrate for CASP3, and CASP3 activity, an important factor for myogenic differentiation, was enhanced by NEK5 cleavage
	after activation by CASP9, CASP3 inhibits ROS production and is required for efficient execution of apoptosis, while effector CASP7 is required for apoptotic cell detachment
	negatively regulated the proliferation of neuronal precursor cells (NPCs) through reducing the phosphorylation of AKT1
	MET can directly inhibit CASP3 by way of a novel mechanism and promote hepatocyte survival
	CASP3, CASP9, and MAPK14 interacted with SLIT1-ROBO2 signaling
	FANCD2 is a novel and specific substrate of CASP3 (cleavage of FANCD2 by CASP3 did not require either the FA core complex or mono-ubiquitylation of FANCD2, and was stimulated by TP53)
	CASP3 activation was mediated by serine protease proteinase 3 (PRTN3), which is present in the cytosol of aging neutrophils (PRTN3 cleaved procaspase-3 at a site upstream of the canonical CASP9 cleavage sit
	MTRNR2L1 protected RPE cells from oxidative stress-induced cell death by STAT3 phosphorylation and inhibiting CASP3 activation

cell & other

REGULATION

activated by	CASP9, CASP8, CASP10
	LPS and rapidly released from HUVEC into the extracellular space. HUVEC escape from cell death and failure of this mechanism may result in endothelial injury/dysfunction

inhibited by	BIRC2, BIRC3,
		BIRC4 (XIAP)
	isatin sulfonamides

Other

inactive form is S-nitrosylated and denitrosylated upon Fas activation

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in prostate cancer (in progression) tumoral somatic mutation       in colon and lung carcinoma

Susceptibility

to lung cancer to Kawasaki disease

Variant & Polymorphism other	GAGC haplotype carrying the variant allele at all of the -928A > G, 77G > A, and 17532A > C loci was associated with a significantly decreased risk of lung cancer compared to the AGGA haplotype carrying no variant alleles
	G to A substitution of one commonly associated SNP located in the 5&
	8242; untranslated region of CASP3 (rs72689236) increases risk of Kawasaki disease

Candidate gene
Marker
Therapy target	mutation V266E activates CASP3 in absence of chain cleavage and is uninhibitable, and thus may lead to novel therapeutic strategies for inducing cell death

ANIMAL & CELL MODELS