Molecular cloning and characterization of a novel caspase-3 variant that attenuates apoptosis induced by proteasome inhibition.
Caspase-3 plays an important role in programmed cell death as an execution-phase caspase in degradation of many substrate proteins. We identified a naturally occurring short caspase-3 variant (caspase-3s) from a human carcinoma cell line that is resulted from alternative mRNA splicing. Analysis of nucleotide sequence reveals a deletion of the exon 6 in this variant that resulted in an altered reading frame in the C-terminus, leading to an altered amino acid sequence and a truncated protein. Caspase-3s shares the same amino acid sequence as caspase-3 in the N-terminus containing the prodomain and the majority of the large subunit. The variant is 95 amino acid residues shorter at the C-terminus and is missing the conserved QACRG sequence in the catalytic site. Caspase-3 and caspase-3s are coexpressed in all human tissues examined. Several cancer cell lines also show coexpression of caspase-3 and caspase-3s, both at the mRNA and protein levels. Overexpression of caspase-3s in 293 cells is more resistant to apoptosis induced by proteasome inhibition. Furthermore, we identified that proteasome inhibition stabilized the level of caspase-3s.
Huang
Y
Y
Department of Neuroscience Therapeutics, Pfizer Global Research & Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Shin
N H
NH
Sun
Y
Y
Wang
K K
KK
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases; D002460:Cell Line; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018076:DNA, Complementary; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D009097:Multienzyme Complexes; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex