Myc downregulation by transforming growth factor β required for activation of the p15(Ink4b) G1 arrest pathway Journal Article
| Authors: | Warner, B. J.; Blain, S. W.; Seoane, J.; Massagué, J. |
| Article Title: | Myc downregulation by transforming growth factor β required for activation of the p15(Ink4b) G1 arrest pathway |
| Abstract: | The antimitogenic action of transforming growth factor β (TGF-β) in epithelial cells involves cyclin-dependent kinase (cdk) inhibitory gene responses and downregulation of c-Myc expression. Although the cdk inhibitory responses are sufficient for G1 arrest, enforced expression of c-Myc prevents G1 arrest by TGF-β. We investigated the basis of this antagonism by using Mv1Lu lung epithelial cell lines that conditionally express levels of human c-Myc. We show that c-Myc prevents induction of the cdk4 inhibitor p15(Ink4b) and the subsequent inhibition of G1 cdks by TGF-β. We assessed the significance of this effect by analyzing the oligomeric state of cdk4 in these cells. In proliferating cells, endogenous cdk4 is distributed among three populations: an abundant high-molecular-mass (>400-kDa) pool of latent cdk4 that serves as a source of cdk4 for cyclin D, a low-abundance pool containing active cyclin D-cdk4 complexes, and an inactive population of monomeric cdk4. Cell stimulation with TGF-β converts the latent and active cdk4 pools into inactive cdk4, an effect that is specifically mimicked by overexpression of p15 but not by other forms of G1 arrest. This process of TGF-β-induced cdk4 inactivation is completely blocked by expression of c- Myc, even though the latent and active cdk4 complexes from c-Myc-expressing cells remain sensitive to dissociation by p15 in vitro, c-Myc causes a small increase in cyclin D levels, but this effect contributes little to the loss of TGF-β responses in these cells. The evidence suggests that c-Myc interferes with TGF-β activation of the p15 G1 arrest pathway. TGF-β must therefore downregulate c-Myc in order to activate this pathway. |
| Keywords: | protein expression; proto-oncogene proteins; nonhuman; cell proliferation; protein analysis; animal cell; animals; cell cycle proteins; cell cycle; complex formation; transforming growth factor beta; cell line; down-regulation; cell population; gene expression regulation; dna; amino acid sequence; molecular sequence data; enzyme inhibitors; genes, myc; carrier proteins; tumor suppressor proteins; protein induction; base sequence; down regulation; cyclin-dependent kinase inhibitor p16; cyclin-dependent kinases; cyclins; cyclin dependent kinase; tetracycline; molecular weight; cell cycle g1 phase; g1 phase; cyclin-dependent kinase 4; cyclin d; mink; cyclin-dependent kinase inhibitor p15; mitosis inhibition; promoter regions (genetics); humans; human; priority journal; article |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 19 |
| Issue: | 9 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 1999-09-01 |
| Start Page: | 5913 |
| End Page: | 5922 |
| Language: | English |
| PUBMED: | 10454538 |
| PROVIDER: | scopus |
| PMCID: | PMC84444 |
| DOI: | 10.1128/MCB.19.9.5913 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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