Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Movement*
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Colon / cytology
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Colon / pathology
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Down-Regulation / genetics
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Enzyme Activation
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GTPase-Activating Proteins / metabolism
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Humans
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Mice
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Models, Biological
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Mutant Proteins / metabolism
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Neoplasms / metabolism*
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Neoplasms / pathology*
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Phosphotyrosine / metabolism
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Protein Transport
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation / genetics
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ras Proteins / metabolism*
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
Substances
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Arhgap5 protein, mouse
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GTPase-Activating Proteins
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Mutant Proteins
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Tumor Suppressor Protein p53
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Phosphotyrosine
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ras Proteins
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rhoA GTP-Binding Protein