Abstract
Activated Ras, operating through the Raf/MEK/ERK pathway, is known to regulate transcription of both Mdm2 and its inhibitor p19ARF, resulting in opposing effects on the tumor suppressor protein p53. We show here that a decrease in Ras in SW480 cells induced either by the Ras inhibitor farnesylthiosalicylic acid (FTS) or by K-Ras antisense oligonucleotides, resulted in a similar increase in p53 protein. The increase in p53 was accompanied by an increase in p21(waf1/cip1) mRNA transcripts and protein. Consistent with the Ras/Raf/MEK/ERK-mediated control of Mdm2, treatment of SW480 cells with the Ras inhibitor FTS caused a marked (80%) decrease in Mdm2, which itself would account for the increase in p53. However, FTS also caused a 1.6-fold increase in p53 mRNA, indicative of a Ras-dependent mechanism that regulates p53 transcription. Thus, oncogenic Ras appears to attenuate p53 in SW480 cells by two independent regulatory mechanisms, the one leading to increased Mdm2-dependent p53 degradation and the other leading to a decrease in p53 transcription.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma / genetics
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Carcinoma / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21
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Down-Regulation / physiology
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Enzyme Inhibitors / pharmacology
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Genes, Regulator / drug effects
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Genes, Regulator / physiology
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Humans
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Nuclear Proteins / metabolism*
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Oligonucleotides, Antisense / pharmacology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Transcriptional Activation / physiology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation / drug effects
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Up-Regulation / physiology
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ras Proteins / antagonists & inhibitors
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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Nuclear Proteins
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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ras Proteins