Antagonistic TSC22D1 variants control BRAFE600-induced senescence
Antagonistic TSC22D1 variants control BRAFE600-induced senescence
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DOI：
10.1038/emboj.2011.95
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发表时间：
2011-05-04
期刊：
影响因子：
11.4
通讯作者：
Peeper, Daniel S.
中科院分区：
文献类型：
--
作者：
Homig-Holzel, Cornelia;Van Doorn, Remco;Peeper, Daniel S.
癌基因诱导的细胞衰老（OIS）是一种日益被认可的肿瘤抑制机制，它限制了体内肿瘤细胞的生长。它依赖于一个复杂的信号网络，但到目前为止只确定了几个组件。基因表达谱显示，在BRAF（E600）诱导的衰老中，转录因子和推定的肿瘤抑制基因TGF β刺激的克隆22（TSC 22 D1）的水平增加> 100倍，在人成纤维细胞和黑素细胞中。只有短的TSC 22 D1转录上调，而大量的蛋白质变体被蛋白酶体降解抑制。TSC 22 D1蛋白变体与其二聚化伴侣TSC 22同源基因1（THG 1）复合，发挥相反的功能，因为选择性耗尽短形式，或相反地，过表达大变体，导致OIS的废除。这伴随着几种炎症因子和p15（INK 4 B）的抑制，TSC 22 D1作为C/EBP β的关键效应子。我们的研究结果表明，拮抗性TSC 22 D1变体的差异调节是OIS建立所必需的，并表明TSC 22家族成员对BRAF（E600）驱动的瘤形成的进展有不同的贡献。The EMBO Journal（2011）30，1753-1765. doi：10.1038/daj.2011.95; 2011年3月29日在线发布
Oncogene-induced cellular senescence (OIS) is an increasingly recognized tumour suppressor mechanism that confines the outgrowth of neoplastic cells in vivo. It relies on a complex signalling network, but only few components have been identified so far. Gene-expression profiling revealed a > 100-fold increase in the levels of the transcription factor and putative tumour suppressor gene TGF beta-stimulated clone 22 (TSC22D1) in BRAF(E600)-induced senescence, in both human fibroblasts and melanocytes. Only the short TSC22D1 transcript was upregulated, whereas the abundance of the large protein variant was suppressed by proteasomal degradation. The TSC22D1 protein variants, in complex with their dimerization partner TSC22 homologue gene 1 (THG1), exerted opposing functions, as selective depletion of the short form, or conversely, overexpression of the large variant, resulted in abrogation of OIS. This was accompanied by the suppression of several inflammatory factors and p15(INK4B), with TSC22D1 acting as a critical effector of C/EBP beta. Our results demonstrate that the differential regulation of antagonistic TSC22D1 variants is required for the establishment of OIS and suggest distinct contributions of TSC22 family members to the progression of BRAF(E600)-driven neoplasia. The EMBO Journal (2011) 30, 1753-1765. doi:10.1038/emboj.2011.95; Published online 29 March 2011