Various p53 mutant proteins differently regulate the ras circuit to induce a cancer-related gene signature

Hilla Solomon, Yosef Buganim, Ira Kogan-Sakin, Leslie Pomeraniec, Yael Assia, Shalom Madar, Ido Goldstein, Ran Brosh, Eyal Kalo, Tsevi Beatus, Naomi Goldfinger, Varda Rotter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Concomitant expression of mutant p53 and oncogenic Ras, leading to cellular transformation, is well documented. However, the mechanisms by which the various mutant p53 categories cooperate with Ras remain largely obscure. From this study we suggest that different mutant p53 categories cooperate with H-Ras in different ways to induce a unique expression pattern of a cancer-related gene signature (CGS). The DNAcontact p53 mutants (p53R248Q and p53R273H) exhibited the highest level of CGS expression by cooperating with NFkB. Furthermore, the Zn+2 region conformational p53 mutants (p53R175H and p53H179R) induced the CGS by elevating H-Ras activity. This elevation in H-Ras activity stemmed from a perturbed function of the p53 transcription target gene, BTG2. By contrast, the L3 loop region conformational mutant (p53G245S) did not affect CGS expression. Our findings were further corroborated in human tumor-derived cell lines expressing Ras and the aforementioned mutated p53 proteins. These data might assist in future tailor-made therapy targeting the mutant p53-Ras axis in cancer.

Original languageAmerican English
Pages (from-to)3144-3152
Number of pages9
JournalJournal of Cell Science
Volume125
Issue number13
DOIs
StatePublished - 1 Jul 2012
Externally publishedYes

Keywords

  • Gain of function
  • Mutant p53
  • Ras

Fingerprint

Dive into the research topics of 'Various p53 mutant proteins differently regulate the ras circuit to induce a cancer-related gene signature'. Together they form a unique fingerprint.

Cite this