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Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: Cleavage of the common α subunit during apoptosis

Oncogene volume 20, pages 358–366 (2001)Cite this article

Abstract

Caspase plays an important role in apoptosis. We report here that farnesyltransferase/geranylgeranyltransferase (FTase/GGTase)-α, a common subunit of FTase (α/βFTase) and GGTase I (α/βGGTase), was cleaved by caspase-3 during apoptosis. FTase/GGTase-α (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-α was cleaved by caspase-3. The common FTase/GGTase-α subunit, but not the β 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 [(D59A)α/βFTase] was resistant to caspase-3. Expression of either the cleavage product (60-379) or anti-sense of FTase/GGTase-α induced cell death in Rat-2/H-ras cells. Furthermore, expression of (D59A)FTase/GGTase-α mutant significantly desensitized cells to etoposide-induced death. Taken together, we suggest that cleavage of prenyltransferase by caspase contributes to the progression of apoptosis.

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Abbreviations

FTase:

farnesyltransferase

FTI:

farnesyltransferase inhibitor

GGTase I:

geranylgeranyltransferase I

YVAD-cmk:

acetyl-Tyr-Val-Ala-Asp-chloromethylketone

DEVD-cho:

acetyl-Asp-Glu-Val-Asp-aldehyde

DMEM:

Dulbecco's Modified Eagle Medium

FCS:

fetal calf serum

PCR:

polymerase chain reaction

SDS–PAGE:

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

PBS:

phosphate buffered saline

HA:

hemagglutinin

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Acknowledgements

We thank S Nagata and J Goldstein for W4 cells and hamster caspase-3 antibody, respectively. We thank N Spoerel for critical reading of this manuscript. This work was supported by Brain Korea 21 project and in part by grants from the KOSEF (97-0401-07-01-5) and Molecular Medicine Research.

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Author notes

  1. Ki-Woo Kim and Hyun-Ho Chung: K-W Kim and H-H Chung contributed equally to this work

Authors and Affiliations

  1. Department of Life Science, Kwangju Institute of Science and Technology, Puk-gu, Kwangju, 500-712, Korea

    Ki-Woo Kim, Chul-Woong Chung, In-Ki Kim, Dong-Gyu Jo, Ha-Na Woo, Yu-Hyun Song, Byung Ju Kim & Yong-Keun Jung

  2. Biotech Research Institute, LG Chem./Research Park, Taejeon, Korea

    Hyun-Ho Chung, Kyung-Duk Moon, Geun-Bae Rha & Jy-Hyun Park

  3. Department of Neuroanatomy, Osaka University Medical School, Osaka, 565, Japan

    Masayuki Miura

  4. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Suyue Wang, Hong Zhu & Junying Yuan

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Kim, KW., Chung, HH., Chung, CW. et al. Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: Cleavage of the common α subunit during apoptosis. Oncogene 20, 358–366 (2001). https://doi.org/10.1038/sj.onc.1204099

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