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.

[1]  V. Rotter,et al.  p53: balancing tumour suppression and implications for the clinic. , 2009, European journal of cancer.

[2]  Judith Campisi,et al.  Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor , 2008, PLoS biology.

[3]  A. Yakovlev,et al.  Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype , 2008, Nature.

[4]  Xuehao Wang,et al.  The level of oncogene H-Ras correlates with tumorigenicity and malignancy , 2008, Cell cycle.

[5]  V. Rotter,et al.  Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II , 2007, Molecular and Cellular Biology.

[6]  D. Auboeuf,et al.  Regulation of H-ras Splice Variant Expression by Cross Talk between the p53 and Nonsense-Mediated mRNA Decay Pathways , 2007, Molecular and Cellular Biology.

[7]  K. Lim,et al.  Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. , 2007, Genes & development.

[8]  Hartmut Land,et al.  Tumor suppressor p53 restricts Ras stimulation of RhoA and cancer cell motility , 2007, Nature Structural &Molecular Biology.

[9]  J. Yates,et al.  PRAK Is Essential for ras-Induced Senescence and Tumor Suppression , 2007, Cell.

[10]  S. Goodman,et al.  Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. , 2006, Journal of the National Cancer Institute.

[11]  Kathleen A. Kennedy,et al.  Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 , 2006, Nature.

[12]  R. Strieter,et al.  CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer , 2006, The Journal of experimental medicine.

[13]  Tsonwin Hai,et al.  Activating Transcription Factor 3, a Stress-inducible Gene, Suppresses Ras-stimulated Tumorigenesis* , 2006, Journal of Biological Chemistry.

[14]  V. Rotter,et al.  hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis. , 2006, Cancer research.

[15]  B. Williams,et al.  A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. , 2006, Genes & development.

[16]  S. Adam,et al.  A network of genetic events sufficient to convert normal human cells to a tumorigenic state. , 2005, Cancer research.

[17]  Andy J. Minn,et al.  Genes that mediate breast cancer metastasis to lung , 2005, Nature.

[18]  Tsonwin Hai,et al.  Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination , 2005, The EMBO journal.

[19]  V. Rotter,et al.  Transcriptional programs following genetic alterations in p53, INK4A, and H-Ras genes along defined stages of malignant transformation. , 2005, Cancer research.

[20]  S. Varambally,et al.  Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). , 2005, Cancer research.

[21]  Natasa Przulj,et al.  High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells , 2005, Science.

[22]  L. Strong,et al.  Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome , 2004, Cell.

[23]  T. Jacks,et al.  Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome , 2004, Cell.

[24]  T. Fox,et al.  The infant mouse as a in vivo model for the detection and study of DNA damage–induced changes in the liver , 2004, Molecular carcinogenesis.

[25]  V. Rotter,et al.  Prolonged culture of telomerase-immortalized human fibroblasts leads to a premalignant phenotype. , 2003, Cancer research.

[26]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[27]  Kazuhiro Usui,et al.  Proinflammatory Cytokine IL-1β Promotes Tumor Growth of Lewis Lung Carcinoma by Induction of Angiogenic Factors: In Vivo Analysis of Tumor-Stromal Interaction1 , 2002, The Journal of Immunology.

[28]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[29]  T. Voeltzel,et al.  The Leukemia-associated Protein Btg1 and the p53-regulated Protein Btg2 Interact with the Homeoprotein Hoxb9 and Enhance Its Transcriptional Activation* , 2000, The Journal of Biological Chemistry.

[30]  D. Pinkel,et al.  The Stromal Proteinase MMP3/Stromelysin-1 Promotes Mammary Carcinogenesis , 1999, Cell.

[31]  J. Jen,et al.  Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe array. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  W. Kabsch,et al.  Guanosine triphosphatase stimulation of oncogenic Ras mutants. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Jen,et al.  Comparison of oncogene mutation detection and telomerase activity for the molecular staging of non-small cell lung cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  B. Chen,et al.  ATF3 Gene , 1996, The Journal of Biological Chemistry.

[35]  G. Boss,et al.  Determination of absolute amounts of GDP and GTP bound to Ras in mammalian cells: comparison of parental and Ras-overproducing NIH 3T3 fibroblasts. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Kinzler,et al.  Molecular determinants of dysplasia in colorectal lesions. , 1994, Cancer research.

[37]  Tsonwin Hai,et al.  ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. , 1994, The Journal of biological chemistry.

[38]  Jonathan A. Cooper,et al.  Mammalian Ras interacts directly with the serine/threonine kinase raf , 1993, Cell.

[39]  B. Neel,et al.  Solubilization and purification of enzymatically active glutathione S-transferase (pGEX) fusion proteins. , 1993, Analytical biochemistry.

[40]  A. Levine,et al.  The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation , 1992, Cell.

[41]  M. Oren,et al.  Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53‐mediated growth arrest. , 1992, The EMBO journal.

[42]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[43]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[44]  J. Jenkins,et al.  Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53 , 1984, Nature.

[45]  P. Gruss,et al.  Participation of p53 cellular tumour antigen in transformation of normal embryonic cells , 1984, Nature.

[46]  V. Rotter,et al.  Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation , 1984, Nature.

[47]  A. Wittinghofer,et al.  GEFs and GAPs: Critical Elements in the Control of Small G Proteins , 2007, Cell.

[48]  J. Downward.  Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[49]  D. Woods,et al.  Regulation of the p53 pathway by Ras, the plot thickens. , 2001, Biochimica et biophysica acta.

[50]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.