JunB suppresses cell proliferation by transcriptional activation of p16INK4a expression
JunB suppresses cell proliferation by transcriptional activation of p16INK4a expression
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DOI：
10.1093/emboj/19.12.2969
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发表时间：
2000-06-15
期刊：
影响因子：
11.4
通讯作者：
Wagner, EF
中科院分区：
文献类型：
--
作者：
Passegué, E;Wagner, EF
在遗传修饰的小鼠成纤维细胞中研究了转录因子JunB在增殖控制中的作用。增加JunB表达诱导高水平的细胞周期蛋白依赖性激酶抑制剂p16（INK 4a），导致原代细胞的过早衰老和3 T3细胞的增殖减少，而缺乏JunB表达导致p16水平降低。此外，在3 T3细胞中，JunB介导的p16诱导完全消除了细胞周期蛋白D相关激酶活性，导致pRb过度磷酸化和G（1）期延长减少。此外，在p16启动子中鉴定了三个API样结合位点，JunB通过这些位点直接激活p16转录。3 T3细胞中JunB表达的升高也抑制了Ras和Src介导的转化和体内肿瘤生长。JunB对细胞增殖的抑制作用显示依赖于p16，因为它不发生在缺乏p16和p19的INK 4a（-/-）成纤维细胞（ARF）中。这些结果表明，p16是JunB的直接转录靶基因，并确定JunB作为细胞增殖的负调控因子。
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 API-like binding sites were identified in the p16 promoter through which JunB directly activates p16 transcription. Elevated JunB expression in 3T3 tells 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.