p53 Regulates the Ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways.
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.
Buganim
Yosef
Y
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Solomon
Hilla
H
Rais
Yoach
Y
Kistner
Daria
D
Nachmany
Ido
I
Brait
Mariana
M
Madar
Shalom
S
Goldstein
Ido
I
Kalo
Eyal
E
Adam
Nitzan
N
Gordin
Maya
M
Rivlin
Noa
N
Kogan
Ira
I
Brosh
Ran
R
Sefadia-Elad
Galit
G
Goldfinger
Naomi
N
Sidransky
David
D
Kloog
Yoel
Y
Rotter
Varda
V
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
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