Rahmouni Souad, Cerignoli Fabio, Alonso Andres, Tsutji Toshiya, Henkens Rachel, Zhu Changjun, Louis-dit-Sully Christine, Moutschen Michel, Jiang Wei, Mustelin Tomas
The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nat Cell Biol. 2006 May;8(5):524-31. doi: 10.1038/ncb1398. Epub 2006 Apr 9.
Protein tyrosine phosphatases regulate important processes in eukaryotic cells and have critical functions in many human diseases including diabetes to cancer. Here, we report that the human Vaccinia H1-related (VHR) dual-specific protein tyrosine phosphatase regulates cell-cycle progression and is itself modulated during the cell cycle. Using RNA interference (RNAi), we demonstrate that cells lacking VHR arrest at the G1-S and G2-M transitions of the cell cycle and show the initial signs of senescence, such as flattening, spreading, appearance of autophagosomes, beta-galactosidase staining and decreased telomerase activity. In agreement with this notion, cells lacking VHR were found to upregulate p21(Cip-Waf1), whereas they downregulated the expression of genes for cell-cycle regulators, DNA replication, transcription and mRNA processing. Loss of VHR also caused a several-fold increase in serum-induced activation of its substrates, the mitogen-activated protein (MAP) kinases Jnk and Erk. VHR-induced cell-cycle arrest was dependent on this hyperactivation of Jnk and Erk, and was reversed by Jnk and Erk inhibition or knock-down. We conclude that VHR is required for cell-cycle progression as it modulates MAP kinase activation in a cell-cycle phase-dependent manner.
蛋白质酪氨酸磷酸酶调节真核细胞中的重要过程，在包括糖尿病到癌症在内的许多人类疾病中具有关键作用。在此，我们报告人类痘苗病毒H1相关（VHR）双特异性蛋白质酪氨酸磷酸酶调节细胞周期进程，并且其自身在细胞周期中受到调节。使用RNA干扰（RNAi），我们证明缺乏VHR的细胞在细胞周期的G1-S和G2-M转换处停滞，并显示出衰老的初始迹象，如扁平化、伸展、自噬体出现、β-半乳糖苷酶染色和端粒酶活性降低。与此观点一致，发现缺乏VHR的细胞上调p21（Cip-Waf1），而它们下调细胞周期调节因子、DNA复制、转录和mRNA加工相关基因的表达。VHR的缺失还导致其底物丝裂原活化蛋白（MAP）激酶Jnk和Erk在血清诱导下的激活增加了几倍。VHR诱导的细胞周期停滞依赖于Jnk和Erk的这种过度激活，并通过Jnk和Erk抑制或敲低而逆转。我们得出结论，VHR是细胞周期进程所必需的，因为它以细胞周期阶段依赖性方式调节MAP激酶的激活。
