K-ras modulates the cell cycle via both positive and negative regulatory pathways.
The effect of activated human K-ras on cell cycle proteins was studied by use of a stable MCF-7 transfectant expressing inducible activated K-ras under the control of a tetracycline (Tet)-responsive promoter. Induction of activated K-ras by Tet withdrawal accelerated cell growth and entry into S-phase. To understand the mechanism(s) by which activated K-ras exerts its effect on the cell cycle, expression of both cell cycle stimulatory proteins as well as cell cycle inhibitors was examined. Upon induction of activated K-ras, several cell cycle stimulators were up-regulated, including cyclins A, D3, and E, and the E2F family of transcription factors, which was accompanied by increased cyclin A-associated kinase activity and E2F transcriptional activity, respectively. Up-regulation of cyclin A occurred at the transcriptional level and in a serum-dependent manner. Furthermore, induction of activated K-ras down-regulated p27Kip1 and up-regulated p53. Up-regulation of p53 was correlated with enhanced p53 transactivation and accompanied by up-regulation of p21Waf1 and Gadd 45, two p53 effectors and negative cell cycle regulators. In addition, activated K-ras up-regulates bcl-2 but has no effect on bax or bcl-x expression. Taken together, these data indicate that activated K-ras affects the cell cycle by modulating both positive and negative cell cycle regulatory pathways.
Fan
J
J
Program for Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Bertino
J R
JR
D000230:Adenocarcinoma / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000502:physiology; D013997:Time Factors; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D018631:ras Proteins / Q000378:metabolism*; D000097642:GADD45 Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D018631:ras Proteins; D000097642:GADD45 Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human