Tumor suppressor p53 restricts Ras stimulation of RhoA and cancer cell motility.
Many features of the cancer cell phenotype emerge as a result of cooperation between multiple oncogenic mutations. Here we show that activated Ras(V12) and loss of p53 function can cooperate to promote cell motility, a feature closely associated with cancer progression to malignancy. Our analysis indicates that Ras(V12) and loss of p53 synergistically induce RhoA activity, revealing a previously unknown role for p53 in tumor suppression. p53 prevents activation of RhoA and thus induction of cell motility by Ras(V12) through a simple signaling circuit, which integrates multiple inputs that converge on RhoA. Our data suggest that p53 suppresses cancer progression to malignancy by modulating the quality of Ras signaling.
Xia
Mingxuan
M
Department of Biomedical Genetics and James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
Land
Hartmut
H
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003106:Colon / Q000166:cytology / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019000:Phosphotyrosine / Q000378:metabolism; D021381:Protein Transport; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C513042:Arhgap5 protein, mouse; D020690:GTPase-Activating Proteins; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D019000:Phosphotyrosine; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein