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J. Biol. Chem., Vol. 279, Issue 2, 1050-1059, January 9, 2004

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High Intensity ras Signaling Induces Premature Senescence by Activating p38 Pathway in Primary Human Fibroblasts^*

Qingdong Deng, Rong Liao, Bai-Lin Wu, and Peiqing Sun

From the Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 91037 and the Departments of Pathology and Laboratory Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Although oncogenic ras plays a pivotal role in neoplastic transformation, it triggers an anti-oncogenic defense mechanism known as premature senescence in normal cells. In this study, we investigated the induction of cellular responses by different expression levels of oncogenic ras in primary human fibroblasts. We found that a moderate, severalfold increase in ras expression promoted cell growth. Further elevation of ras expression initially enhanced proliferation but eventually induced p16^INK4A expression and senescence. The induction of these opposing cellular responses by ras signals of different intensity was achieved through differential activation of the MAPK pathways that mediated these responses. Whereas moderate ras activities only stimulated the mitogenic MEK-ERK pathway, high intensity ras signals induced MEK and ERK to higher levels, leading to stimulation of the MKK3/6-p38 pathway, which had been shown previously to act downstream of Ras-MEK to trigger the senescence response. Thus, these studies have revealed a mechanism for the differential effects of ras on cell proliferation. Furthermore, moderate ras activity mediated transformation in cooperation with E6E7 and hTERT, suggesting that a moderate intensity ras signal can provide sufficient oncogenic activities for tumorigenesis. This result also implies that the ability of ras to promote proliferation and oncogenic transformation can be uncoupled with that to induce senescence in cell culture and that the development of tumors with relatively low ras activities may not need to acquire genetic alterations that bypass premature senescence.

Received for publication, August 6, 2003 , and in revised form, October 24, 2003.

^* This is Scripps publication number 14303-MB. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

New Scholar of the Ellison Medical Foundation ands supported in part by a grant from the National Institutes of Health. To whom correspondence should be addressed: Dept, of Molecular Biology, MB-41, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 91037. Tel.: 858-784-9710; Fax: 858-784-9067; E-mail: pqsun{at}scripps.edu.

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