Protein 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, 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.
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This work was supported by Rotary International, the Van Beirs Foundation, Centre Anticancéreux près L'Université de Liège, the Spanish Ministry of Education and Culture, the Plan Nacional de Salud y Farmacia (SAF 2003-05194) and the National Institutes of Health (AI35603).
The authors declare no competing financial interests.
Supplementary Figures S1, S2, S3 and S4, Supplementary Table 1 and 2 (PDF 3691 kb)
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