Frippiat C, Chen Q M, Remacle J, Toussaint O
University of Namur (FUNDP), Unit of Cellular Biochemistry & Biology, 61, Rue de Bruxelles, B-5000, Namur, Belgium.
Exp Gerontol. 2000 Sep;35(6-7):733-45. doi: 10.1016/s0531-5565(00)00167-4.
Many biomarkers of replicative senescence appear in stress-induced premature senescence (SIPS) of human diploid fibroblasts (HDFs). The mRNA level of key cell cycle regulators was studied in H(2)O(2)-induced premature senescence of HDFs expressing or not the papillomavirus E6 and E7 proteins, which enhanced, respectively, the proteolysis of p53 and Rb. The CdKI's p21(waf-1) and p16(Ink-4a) were found overexpressed in H(2)O(2)-induced premature senescence, while p19(Ink-4d)and p27(Kip-1) were repressed. The results obtained in E6 HDFs suggest that p21(waf-1) and p16(Ink-4a) overexpressions are p53-independent, while p27(Kip-1) and p19(Ink-4d) down-regulations are p53-dependent.E6 regulated Rb, p130, p53 and p16(Ink-4a) mRNA level in non-stressing conditions, and regulated p130, p107, p53, p19(Ink-4d), p27(Kip-1) mRNA level in SIPS. SIPS modified the E6-mediated regulatory control on p107, p16(Ink-4a), p19(Ink-4d) and p27(Kip-1) mRNA level, when compared to normal conditions.E7 regulated the mRNA level of all the genes studied, in all conditions, suggesting that the Rb family or other E7-interacting proteins might modify the expression of these genes. SIPS modified strongly the E7-mediated regulatory control on p107, p16(Ink-4a), p19(Ink-4d), p27(Kip-1), p21(Waf-1) and Rb mRNA level, when compared to normal conditions. Further work is ongoing to test whether this E7-mediated regulatory control takes place through interactions with Rb or other E7-interacting proteins.
许多复制性衰老的生物标志物出现在人二倍体成纤维细胞（HDFs）的应激诱导早衰（SIPS）中。在表达或不表达乳头瘤病毒E6和E7蛋白的HDFs的H₂O₂诱导早衰中，研究了关键细胞周期调节因子的mRNA水平，E6和E7蛋白分别增强了p53和Rb的蛋白水解。发现细胞周期蛋白依赖性激酶抑制因子p21（waf-1）和p16（Ink-4a）在H₂O₂诱导的早衰中过表达，而p19（Ink-4d）和p27（Kip-1）被抑制。在E6 HDFs中获得的结果表明，p21（waf-1）和p16（Ink-4a）的过表达不依赖于p53，而p27（Kip-1）和p19（Ink-4d）的下调依赖于p53。E6在非应激条件下调节Rb、p130、p53和p16（Ink-4a）的mRNA水平，并在SIPS中调节p130、p107、p53、p19（Ink-4d）、p27（Kip-1）的mRNA水平。与正常条件相比，SIPS改变了E6介导的对p107、p16（Ink-4a）、p19（Ink-4d）和p27（Kip-1）mRNA水平的调控。在所有条件下，E7调节所有研究基因的mRNA水平，这表明Rb家族或其他与E7相互作用的蛋白可能会改变这些基因的表达。与正常条件相比，SIPS强烈改变了E7介导的对p107、p16（Ink-4a）、p19（Ink-4d）、p27（Kip-1）、p21（Waf-1）和Rb mRNA水平的调控。正在进行进一步的研究，以测试这种E7介导的调控是否通过与Rb或其他与E7相互作用的蛋白相互作用而发生。
