JunB suppresses cell proliferation by transcriptional activation of p16INK4a expression

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Abstract
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 G1‐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.