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J. Biol. Chem. 275 (46): 35669-35672

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Ras Uses the Novel Tumor Suppressor RASSF1 as an Effector to Mediate Apoptosis*

Michele D. Vos, Chad A. Ellis, Aaron Bell, Michael J. Birrer, , and Geoffrey J. Clark{ddagger}

From the Department of Cell and Cancer Biology, NCI, National Institutes of Health, Rockville, Maryland 20850-3300

ABSTRACT Back to Top

Abstract: Although activated Ras proteins are usually associated with driving growth and transformation, they may also induce senescence, apoptosis, and terminal differentiation. The subversion of these anti-neoplastic effects during Ras-dependent tumor development may be as important as the acquisition of the pro-neoplastic effects. None of the currently identified potential Ras effector proteins can satisfactorily explain the apoptotic action of Ras. Consequently, we have sought to identify novel Ras effectors that may be responsible for apoptosis induction. By examining the EST data base, we identified a potential Ras association domain in the tumor suppressor RASSF1. We now show that RASSF1 binds Ras in a GTP-dependent manner, both in vivo and directlyin vitro. Moreover, activated Ras enhances and dominant negative Ras inhibits the cell death induced by transient transfection of RASSF1 into 293-T cells. This cell death appears to be apoptotic in nature, as RASSF1-transfected 293-T cells exhibit membrane blebbing and can be rescued by the addition of a caspase inhibitor. Thus, the RASSF1 tumor suppressor may serve as a novel Ras effector that mediates the apoptotic effects of oncogenic Ras.

Received for publication July 14, 2000. Revision received September 18, 2000.

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Frequent Epigenetic Inactivation of RASSF1A in Human Bladder Carcinoma.
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Cancer Res. 61, 6688-6692
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The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis.
K. Dreijerink, E. Braga, I. Kuzmin, L. Geil, F.-M. Duh, D. Angeloni, B. Zbar, M. I. Lerman, E. J. Stanbridge, J. D. Minna, et al. (2001)
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   Abstract »    Full Text »    PDF »
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Hypermethylation of the CpG Island of Ras Association Domain Family 1A (RASSF1A), a Putative Tumor Suppressor Gene from the 3p21.3 Locus, Occurs in a Large Percentage of Human Breast Cancers.
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Cancer Res. 61, 3105-3109
   Abstract »    Full Text »
The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis.
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PNAS 98, 7504-7509
   Abstract »    Full Text »    PDF »

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