JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression.
A role for the transcription factor JunB in proliferation control was investigated in genetically modified mouse fibroblasts. Increased JunB expression induced high levels of the cyclin-dependent kinase inhibitor p16(INK4a), leading to premature senescence in primary cells and reduced proliferation in 3T3 cells, whereas lack of JunB expression results in decreased p16 levels. Furthermore, JunB-mediated p16 induction in 3T3 cells completely abolished cyclin D-associated kinase activity, resulting in reduced pRb hyperphosphorylation and G(1)-phase extension. Moreover, three AP1-like binding sites were identified in the p16 promoter through which JunB directly activates p16 transcription. Elevated JunB expression in 3T3 cells also inhibited Ras- and Src-mediated transformation and tumour growth in vivo. The suppressive effect of JunB on cell proliferation was shown to be dependent on p16 since it did not occur in INK4a(-/-) fibroblasts that lack both p16 and p19(ARF). These results demonstrate that p16 is a direct transcriptional target gene of JunB and identify JunB as a negative regulator of cell proliferation.
Passegué
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Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Wagner
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D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D056741:Cyclin D; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins; D005347:Fibroblasts / Q000166:cytology; D016193:G1 Phase; D051379:Mice; D008822:Mice, Transgenic; D015689:Oncogene Protein p21(ras); D015688:Oncogene Protein pp60(v-src); D011401:Promoter Regions, Genetic; D011494:Protein Kinases; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
D002352:Carrier Proteins; D056741:Cyclin D; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D011494:Protein Kinases; D015688:Oncogene Protein pp60(v-src); D018844:Cyclin-Dependent Kinases; D015689:Oncogene Protein p21(ras)