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Molecular and Cellular Biology, May 2002, p. 3389-3403, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3389-3403.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence{dagger}

Weiping Wang,1 Joan X. Chen,1,{ddagger} Rong Liao,1 Qingdong Deng,1 Jennifer J. Zhou,1 Shuang Huang,2 and Peiqing Sun1*

Department of Molecular Biology,1 Department of Immunology, The Scripps Research Institute, La Jolla, California 910372

Received 28 September 2001/ Returned for modification 5 November 2001/ Accepted 4 February 2002

In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.

* Corresponding author. Mailing address: Department of Molecular Biology, MB-41, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 91037. Phone: (858) 784-9710. Fax: (858) 784-9985. E-mail: pqsun{at}scripps.edu.

{dagger} This is Scripps manuscript no. 14467-MB.

{ddagger} Present address: Aurora Biosciences Corporation, San Diego, CA 92121.

Molecular and Cellular Biology, May 2002, p. 3389-3403, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3389-3403.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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