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Molecular and Cellular Biology, March 2006, p. 2202-2214, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2202-2214.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Molecular Scaffold Kinase Suppressor of Ras 1 Is a Modifier of Ras^V12-Induced and Replicative Senescence

Robert L. Kortum,¹ Heidi J. Johnson,¹ Diane L. Costanzo,¹ Deanna J. Volle,¹ Gina L. Razidlo,¹ Angela M. Fusello,² Andrey S. Shaw,² and Robert E. Lewis^1*

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696,¹ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110²

Received 13 July 2005/ Returned for modification 16 August 2005/ Accepted 3 January 2006

In primary mouse embryo fibroblasts (MEFs), oncogenic Ras induces growth arrest via Raf/MEK/extracellular signal-regulated kinase (ERK)-mediated activation of the p19^ARF/p53 and INK4/Rb tumor suppressor pathways. Ablation of these same pathways causes spontaneous immortalization in MEFs, and oncogenic transformation by Ras requires ablation of one or both of these pathways. We show that Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK cascade, is necessary for Ras^V12-induced senescence, and its disruption enhances primary MEF immortalization. Ras^V12 failed to induce p53, p19^ARF, p16^INK4a, and p15^INK4b expression in KSR1^–/– MEFs and increased proliferation instead of causing growth arrest. Reintroduction of wild-type KSR1, but not a mutated KSR1 construct unable to bind activated ERK, rescued Ras^V12-induced senescence. On continuous culture, deletion of KSR1 accelerated the establishment of spontaneously immortalized cultures and increased the proportion of cultures escaping replicative crisis. Despite enhancing escape from both Ras^V12-induced and replicative senescence, however, both primary and immortalized KSR1^–/– MEFs are completely resistant to Ras^V12-induced transformation. These data show that escape from senescence is not necessarily a precursor for oncogenic transformation. Furthermore, these data indicate that KSR1 is a member of a unique class of proteins whose deletion blocks both senescence and transformation.

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* Corresponding author. Mailing address: University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, Omaha, NE 68198-7696. Phone: (402) 559-8290. Fax: (402) 559-3739. E-mail: rlewis{at}unmc.edu.

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Molecular and Cellular Biology, March 2006, p. 2202-2214, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2202-2214.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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