Colorectal Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Colorectal Cancer, including details on symptoms, genetics, screening, treatment, information.

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

Halaschek-Wiener J, Wacheck V, Kloog Y, Jansen B

Department of Clinical Pharmacology, Section of Experimental Oncology and Molecular Pharmacology, University of Vienna, Währinger Gürtel 18-20, A-1090, Austria. julius.halaschek-wiener@univie.ac.at

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.

Published 31 August 2004 in Cell Signal, 16(11): 1319-27.
Full-text of this article is available online (may require subscription).

© 2004-2008 Colorectal Cancer Research Today. All Rights Reserved.