Ras inhibition leads to transcriptional activation of p53 and down-regulation of Mdm2: two mechanisms that cooperatively increase p53 function in colon cancer cells.
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.
Halaschek-Wiener
Julius
J
Department of Clinical Pharmacology, Section of Experimental Oncology and Molecular Pharmacology, University of Vienna, Währinger Gürtel 18-20, A-1090, Austria. julius.halaschek-wiener@univie.ac.at
Wacheck
Volker
V
Kloog
Yoel
Y
Jansen
Burkhard
B
D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005809:Genes, Regulator / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D018631:ras Proteins