title: p53 Regulates the Ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways.
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-Ras(G12V) 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-Ras(G12V), 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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Buganim
authors.forename: Hilla
authors.initials: H
authors.lastname: Solomon
authors.forename: Yoach
authors.initials: Y
authors.lastname: Rais
authors.forename: Daria
authors.initials: D
authors.lastname: Kistner
authors.forename: Ido
authors.initials: I
authors.lastname: Nachmany
authors.forename: Mariana
authors.initials: M
authors.lastname: Brait
authors.forename: Shalom
authors.initials: S
authors.lastname: Madar
authors.forename: Ido
authors.initials: I
authors.lastname: Goldstein
authors.forename: Eyal
authors.initials: E
authors.lastname: Kalo
authors.forename: Nitzan
authors.initials: N
authors.lastname: Adam
authors.forename: Maya
authors.initials: M
authors.lastname: Gordin
authors.forename: Noa
authors.initials: N
authors.lastname: Rivlin
authors.forename: Ira
authors.initials: I
authors.lastname: Kogan
authors.forename: Ran
authors.initials: R
authors.lastname: Brosh
authors.forename: Galit
authors.initials: G
authors.lastname: Sefadia-Elad
authors.forename: Naomi
authors.initials: N
authors.lastname: Goldfinger
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D017874:Immediate-Early Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins