Nature Cell Biology 8, 524 - 531 (2006)
Published online: 9 April 2006; | doi:10.1038/ncb1398
Loss of the VHR dual-specific phosphatase causescell-cycle arrest and senescenceSouad Rahmouni1, 2, Fabio Cerignoli1, Andres Alonso1, 3, Toshiya Tsutji1, Rachel Henkens2, Changjun Zhu1, Christine Louis-dit-Sully1, Michel Moutschen2, Wei Jiang1
& Tomas Mustelin11
The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. 2
University of Liège, B35, Avenue de l'Hôpital, 3, 4000 Liège 1, Belgium. 3
Instituto de Biologia y Genetica Molecular, C/Sanz y Forés, s/n, 47003, Valladolid, Spain.
Correspondence should be addressed to Tomas Mustelin tmustelin@burnham-inst.org VHRJnkErkp38MekProtein tyrosine phosphatases regulate important processes in eukaryotic cells and have critical functions in many human diseases including diabetes to cancer1,
2,
3. 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,  -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.
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