title: Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence.
abstract: 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.
authors.affiliation: The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.forename: Fabio
authors.initials: F
authors.lastname: Cerignoli
authors.forename: Andres
authors.initials: A
authors.lastname: Alonso
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tsutji
authors.forename: Rachel
authors.initials: R
authors.lastname: Henkens
authors.forename: Changjun
authors.initials: C
authors.lastname: Zhu
authors.forename: Christine
authors.initials: C
authors.lastname: Louis-dit-Sully
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
mesh_terms: D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D002522:Chlorocebus aethiops; D004247:DNA / Q000096:biosynthesis; D054640:Dual Specificity Phosphatase 3; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016196:S Phase / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; D017027:Protein Tyrosine Phosphatases