Characterization of a novel isoform of caspase-9 that inhibits apoptosis.
We have identified a novel isoform of rat caspase-9 in which the C terminus of full-length caspase-9 is replaced with an alternative peptide sequence. Casp-9-CTD (where CTD is carboxyl-terminal divergent) is expressed in multiple tissues, with the relative highest expression observed in ovary and heart. Casp-9-CTD was found primarily in the cytoplasm and was not detected in the nucleus. Structural predictions suggest that in contrast to full-length caspase-9, casp-9-CTD will not be processed. Our model is supported by reduced protease activity of casp-9-CTD preparations in vitro and by the lack of detectable processing of casp-9-CTD proenzyme or the induction of cell death following transfection into cells. Both neuronal and non-neuronal cell types transfected with casp-9-CTD were resistant to death evoked by trophic factor deprivation or DNA damage. In addition, cytosolic lysates prepared from cells permanently expressing exogenous casp-9-CTD were resistant to caspase induction by cytochrome c in reconstitution assays. Taken together, our observations indicate that casp-9-CTD acts as a dominant-negative variant. Its expression in various tissues indicates a physiological role in regulating cell death.
Department of Pathology, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. jma14@columbia.edu
J M
JM
Angelastro
N Y
NY
Moon
D X
DX
Liu
A S
AS
Yang
L A
LA
Greene
T F
TF
Franke
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D016716:PC12 Cells; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D017931:DNA Primers; D011994:Recombinant Proteins; D004247:DNA; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases