Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells
Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells
复制标题
DOI：
10.1074/jbc.m405419200
复制
发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Weber, DJ
中科院分区：
文献类型：
--
作者：
Lin, J;Yang, QY;Weber, DJ
S100钙结合蛋白，如S100B，在原发恶性黑色素瘤中升高，并被用作该肿瘤和许多其他癌症的标志物。在这些癌细胞中，野生型P53蛋白水平相对较低(即与没有S100B的细胞相比)，但当引入S100B的反义RNA时，野生型P53蛋白水平升高。这一结果表明S100B下调了P53的表达，这与先前观察到的P53和S100B瞬时共转染中P53蛋白水平的大幅下降是一致的(Lin，J.，Blake，M.，Tang，C.，Zimmer，D.，RuStandi，R.，Weber，D.J.和Carrier，F.(2001)J.Biol)。化学。276、35037-35041)。原代恶性黑色素瘤细胞中P53的下调可能是通过免疫共沉淀实验观察到的与S100B的直接相互作用的结果。此外，P53与S100B启动子的区域结合，其中一个区域与20个核苷酸的P53结合的共识DNA序列完全匹配。因此，当P53水平增加时，它通过上调S100B的转录来促进自身的死亡，这是负反馈循环的一部分。这与对另一种下调P53的蛋白质Hdm2(人类双重突变2)的发现类似。
S100 calcium-binding proteins such as S100B are elevated in primary malignant melanoma and are used as markers for this and numerous other cancers. Wild-type p53 protein levels are relatively low in these cancer cells (i.e. when compared with cells without S100B) but are elevated when RNA antisense to S100B is introduced. This result implicates S100B in the down-regulation of p53 and is consistent with the large decreases in p53 protein levels observed previously in transient co-transfections of p53 and S100B (Lin, J., Blake, M., Tang, C., Zimmer, D., Rustandi, R. R., Weber, D. J., and Carrier, F. (2001) J. Biol. Chem. 276, 35037-35041). Down-regulation of p53 in primary malignant melanoma cells is likely the result of a direct interaction with S100B, which was observed by co-immunoprecipitation experiments. Furthermore, p53 binds regions of the S100B promoter, one of which matches the 20-nucleotide p53-binding consensus DNA sequence perfectly. Therefore, when p53 levels increase, it contributes to its own demise by up-regulating the transcription of S100B as part of a negative feedback loop. This is analogous to what is found for another protein that down-regulates p53, namely hdm2 (human double mutant 2).