Loss of the VHR dual-specific phosphatase causescell-cycle arrest and senescence

• Published in: Nature cell biology Vol. 8; no. 5; pp. 524 - 531
• Main Authors: Mustelin, Tomas, Rahmouni, Souad, Cerignoli, Fabio, Alonso, Andres, Tsutji, Toshiya, Henkens, Rachel, Zhu, Changjun, Louis-dit-Sully, Christine, Moutschen, Michel, Jiang, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.05.2006
• Subjects: Cell activation; Cell cycle; Cell division; Cyclin-dependent kinase inhibitor p21; Deoxyribonucleic acid; Diabetes mellitus; DNA; DNA biosynthesis; Extracellular signal-regulated kinase; Galactosidase; Gene expression; Kinases; MAP kinase; Microscopy; mRNA processing; Phagosomes; Phosphatase; Protein folding; Protein synthesis; Protein-tyrosine-phosphatase; Proteins; RNA-mediated interference; Senescence; Substrates; Telomerase; Tyrosine; Vaccinia; β-Galactosidase
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb1398

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, β-galactosidase staining and decreased telomerase activity. In agreement with this notion, cells lacking VHR were found to upregulate p21Cip-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.