title: Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: cleavage of the common alpha subunit during apoptosis.
abstract: Caspase plays an important role in apoptosis. We report here that farnesyltransferase/geranylgeranyltransferase (FTase/GGTase)-alpha, a common subunit of FTase (alpha/beta(FTase)) and GGTase I (alpha/beta(GGTase)), was cleaved by caspase-3 during apoptosis. FTase/GGTase-alpha (49 kDa) was cleaved to 35 kDa (p35) in the Rat-2/H-ras, W4 and Rat-1 cells treated with FTase inhibitor (LB42708), anti-Fas antibody and etoposide, respectively. This cleavage was inhibited by caspase-inhibitors (YVAD-cmk, DEVD-cho). Serial N-terminal deletions and site-directed mutagenesis showed that Asp59 of FTase/GGTase-alpha was cleaved by caspase-3. The common FTase/GGTase-alpha subunit, but not the beta subunits, of the FTase or GGTase I protein complexes purified from baculovirus-infected SF-9 cells was cleaved to be inactivated by purified caspase-3. In contrast, FTase mutant protein complex [(D(59)A)alpha/beta(FTase)] was resistant to caspase-3. Expression of either the cleavage product (60-379) or anti-sense of FTase/GGTase-alpha induced cell death in Rat-2/H-ras cells. Furthermore, expression of (D(59)A)FTase/GGTase-alpha mutant significantly desensitized cells to etoposide-induced death. Taken together, we suggest that cleavage of prenyltransferase by caspase contributes to the progression of apoptosis.
authors: Department of Life Science, Kwangju Institute of Science and Technology, Puk-gu, Kwangju 500-712, Korea.
authors: K W
authors: KW
authors: Kim
authors: H H
authors: HH
authors: Chung
authors: C W
authors: CW
authors: Chung
authors: I K
authors: IK
authors: Kim
authors: M
authors: M
authors: Miura
authors: S
authors: S
authors: Wang
authors: H
authors: H
authors: Zhu
authors: K D
authors: KD
authors: Moon
authors: G B
authors: GB
authors: Rha
authors: J H
authors: JH
authors: Park
authors: D G
authors: DG
authors: Jo
authors: H N
authors: HN
authors: Woo
authors: Y H
authors: YH
authors: Song
authors: B J
authors: BJ
authors: Kim
authors: J
authors: J
authors: Yuan
authors: Y K
authors: YK
authors: Jung
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001224:Aspartic Acid / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D010449:Peptide Mapping; D017368:Protein Prenylation; D021122:Protein Subunits
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D009842:Oligopeptides; D021122:Protein Subunits; C108637:aspartyl-glutamyl-valyl-aspartal; D001224:Aspartic Acid; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases