Ras inhibition leads to transcriptional activation of p53 and down-regulation of Mdm2: Two mechanisms that cooperatively increase p53 function in colon cancer cells

Julius Halaschek-Wiener*, Volker Wacheck, Yoel Kloog, Burkhard Jansen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Activated Ras, operating through the Raf/MEK/ERK pathway, is known to regulate transcription of both Mdm2 and its inhibitor p19ARF, resulting in opposing effects on the tumor suppressor protein p53. We show here that a decrease in Ras in SW480 cells induced either by the Ras inhibitor farnesylthiosalicylic acid (FTS) or by K-Ras antisense oligonucleotides, resulted in a similar increase in p53 protein. The increase in p53 was accompanied by an increase in p21(waf1/cip1) mRNA transcripts and protein. Consistent with the Ras/Raf/MEK/ERK-mediated control of Mdm2, treatment of SW480 cells with the Ras inhibitor FTS caused a marked (80%) decrease in Mdm2, which itself would account for the increase in p53. However, FTS also caused a 1.6-fold increase in p53 mRNA, indicative of a Ras-dependent mechanism that regulates p53 transcription. Thus, oncogenic Ras appears to attenuate p53 in SW480 cells by two independent regulatory mechanisms, the one leading to increased Mdm2-dependent p53 degradation and the other leading to a decrease in p53 transcription.

Original languageEnglish
Pages (from-to)1319-1327
Number of pages9
JournalCellular Signalling
Volume16
Issue number11
DOIs
StatePublished - Nov 2004

Funding

FundersFunder number
Bürgermeister Fonds der Stadt Wien
Hochschuljubiläumsstiftung
Hygiene Fund
Niarchos Foundation
Virology Fund
Austrian Science Fund
Oesterreichische Nationalbank
Kamillo Eisner Stiftung

    Keywords

    • ASO
    • FTIs
    • FTS
    • MAPK
    • MEK
    • Mdm2
    • Ras
    • Real-time PCR
    • S-trans,trans-farnesylthiosalicylic acid
    • SW480
    • antisense oligonucleotide
    • farnesyl transferase inhibitors
    • mitogen-activated protein kinase/ERK kinase
    • p21
    • p53

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