Mathieu Vernier

Publications (2)19.63 Total impact

• Article: Retinoblastoma-independent regulation of cell proliferation and senescence by the p53-p21 axis in lamin A /C-depleted cells.

  Olga Moiseeva, Véronique Bourdeau, Mathieu Vernier, Marie-Christine Dabauvalle, Gerardo Ferbeyre
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  ABSTRACT: The expression of A-type lamin is downregulated in several cancers, and lamin defects are the cause of several diseases including a form of accelerated aging. We report that depletion of lamin A/C expression in normal human cells leads to a dramatic downregulation of the Rb family of tumor suppressors and a defect in cell proliferation. Lamin A/C-depleted cells exhibited a flat morphology and accumulated markers of cellular senescence. This senescent phenotype was accompanied by engagement of the p53 tumor suppressor and induction of the p53 target gene p21 and was prevented by small hairpin RNAs against p53, p21, or by the oncoprotein Mdm2. The expression of E2F target genes, normally required for cell cycle progression, was downregulated after lamin A/C depletion but restored after the inactivation of p53. A similar senescence response was observed in myoblasts from a patient with a lamin A mutation causing muscular dystrophy. We thus reveal a previously unnoticed mechanism of controlling cell cycle genes expression, which depends on p53 but does not require the retinoblastoma family of tumor suppressors and that can be relevant to understand the pathogenesis of laminopathies and perhaps aging.
  Aging cell 05/2011; 10(5):789-97. · 7.55 Impact Factor
• Article: Regulation of E2Fs and senescence by PML nuclear bodies.

  Mathieu Vernier, Véronique Bourdeau, Marie-France Gaumont-Leclerc, Olga Moiseeva, Virginie Bégin, Fred Saad, Anne-Marie Mes-Masson, Gerardo Ferbeyre
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  ABSTRACT: The tumor suppressor PML (promyelocytic leukemia protein) regulates cellular senescence and terminal differentiation, two processes that implicate a permanent exit from the cell cycle. Here, we show that the mechanism by which PML induces a permanent cell cycle exit and activates p53 and senescence involves a recruitment of E2F transcription factors bound to their promoters and the retinoblastoma (Rb) proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1α. Blocking the functions of the Rb protein family or adding back E2Fs to PML-expressing cells can rescue their defects in E2F-dependent gene expression and cell proliferation, inhibiting the senescent phenotype. In benign prostatic hyperplasia, a neoplastic disease that displays features of senescence, PML was found to be up-regulated and forming nuclear bodies. In contrast, PML bodies were rarely visualized in prostate cancers. The newly defined PML/Rb/E2F pathway may help to distinguish benign tumors from cancers, and suggest E2F target genes as potential targets to induce senescence in human tumors.
  Genes & development 01/2011; 25(1):41-50. · 12.08 Impact Factor