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

Nature Cell Biology volume 8, pages 524–531 (2006)Cite this article

An Erratum to this article was published on 01 June 2006

Abstract

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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Figure 1: Expression of VHR during cell-cycle progression in HeLa cells.
Figure 2: Loss of VHR results in altered morphology and beginning cell senescence.
Figure 3: Loss of VHR results in absence of cells in S phase and M phase.
Figure 4: Loss of VHR augments activation of Erk and Jnk.
Figure 5: Reduction of Mek and Jnk levels can overcome the cell-cycle arrest caused by loss of VHR.

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Acknowledgements

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).

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Authors and Affiliations

  1. The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA

    Souad Rahmouni, Fabio Cerignoli, Andres Alonso, Toshiya Tsutji, Changjun Zhu, Christine Louis-dit-Sully, Wei Jiang & Tomas Mustelin

  2. University of Liège, B35, Avenue de l'Hôpital, 3, 4000 Liège 1, Belgium

    Souad Rahmouni, Rachel Henkens & Michel Moutschen

  3. Instituto de Biologia y Genetica Molecular, C/Sanz y Forés, s/n, Valladolid, 47003, Spain

    Andres Alonso

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Supplementary Figures S1, S2, S3 and S4, Supplementary Table 1 and 2 (PDF 3691 kb)

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Rahmouni, S., Cerignoli, F., Alonso, A. et al. Loss of the VHR dual-specific phosphatase causescell-cycle arrest and senescence. Nat Cell Biol 8, 524–531 (2006). https://doi.org/10.1038/ncb1398

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