The molecular scaffold kinase suppressor of Ras 1 is a modifier of Ras V12-induced and replicative senescence

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

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Abstract

In primary mouse embryo fibroblasts (MEFs), oncogenic Ras induces growth arrest via Raf/MEK/extracellular signal-regulated kinase (ERK)-mediated activation of the p19ARF/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 RasV12-induced senescence, and its disruption enhances primary MEF immortalization. Ras V12 failed to induce p53, p19ARF, p16INK4a, and p15INK4b 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 RasV12-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 RasV12-induced and replicative senescence, however, both primary and immortalized KSR1-/- MEFs are completely resistant to RasV12-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.

Original languageEnglish (US)
Pages (from-to)2202-2214
Number of pages13
JournalMolecular and cellular biology
Volume26
Issue number6
DOIs
StatePublished - Mar 1 2006

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Cell Aging
Embryonic Structures
Fibroblasts
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase Kinases
Growth
KSR-1 protein kinase
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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The molecular scaffold kinase suppressor of Ras 1 is a modifier of Ras V12-induced and replicative senescence. / Kortum, Robert L.; Johnson, Heidi J.; Costanzo, Diane L.; Volle, Deanna J.; Razidlo, Gina L.; Fusello, Angela M.; Shaw, Andrey S.; Lewis, Robert E.

In: Molecular and cellular biology, Vol. 26, No. 6, 01.03.2006, p. 2202-2214.

Research output: Contribution to journalArticle

Kortum, Robert L. ; Johnson, Heidi J. ; Costanzo, Diane L. ; Volle, Deanna J. ; Razidlo, Gina L. ; Fusello, Angela M. ; Shaw, Andrey S. ; Lewis, Robert E. / The molecular scaffold kinase suppressor of Ras 1 is a modifier of Ras V12-induced and replicative senescence. In: Molecular and cellular biology. 2006 ; Vol. 26, No. 6. pp. 2202-2214.
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