p53 regulates the ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways

Yosef Buganim, Hilla Solomon, Yoach Rais, Daria Kistner, Ido Nachmany, Mariana Brait, Shalom Madar, Ido Goldstein, Eyal Kalo, Nitzan Adam, Maya Gordin, Noa Rivlin, Ira Kogan, Ran Brosh, Galit Sefadia-Elad, Naomi Goldfinger, David Sidransky, Yoel Kloog, Varda Rotter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

In this study, we focus on the analysis of a previously identified cancer-related gene signature (CGS) that underlies the cross talk between the p53 tumor suppressor and Ras oncogene. CGS consists of a large number of known Ras downstream target genes that were synergistically upregulated by wild-type p53 loss and oncogenic H-RasG12V expression. Here we show that CGS expression strongly correlates with malignancy. In an attempt to elucidate the molecular mechanisms underling the cooperation between p53 loss and oncogenic H-RasG12V, we identified distinguished pathways that may account for the regulation of the expression of the CGS. By knocking-down p53 or by expressing mutant p53, we revealed that p53 exerts its negative effect by at least two mechanisms mediated by its targets B-cell translocation gene 2 (BTG2) and activating transcription factor 3 (ATF3). Whereas BTG2 binds H-Ras G12V and represses its activity by reducing its GTP loading state, which in turn causes a reduction in CGS expression, ATF3 binds directly to the CGS promoters following p53 stabilization and represses their expression. This study further elucidates the molecular loop between p53 and Ras in the transformation process.

Original languageAmerican English
Pages (from-to)2274-2284
Number of pages11
JournalCancer Research
Volume70
Issue number6
DOIs
StatePublished - 15 Mar 2010
Externally publishedYes

Fingerprint

Dive into the research topics of 'p53 regulates the ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways'. Together they form a unique fingerprint.

Cite this