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Nouvelles fonctions de p21Cip1 dans la dynamique cytosquelettique des cellules épithéliales mammaires humaines

Abstract : CDKN1A gene was initially identified as a target of the tumor suppressor p53. The ability to inhibitcyclin-dependant kinase and PCNA activities confers to its product, p21Cip1 (p21), strong antiproliferativeproperties. Moreover, p21 is frequently inactivated in epithelial cancers. Progression ofthese malignancies is also associated with disorganized tissue architecture, invasion and metastaticdissemination. These processes involve major cytoskeletal reorganization associated withtransformation of adhesion and migration properties. Still, the role of p21 in cytoskeletal dynamics innormal epithelial cell has never been addressed. Here we show that p21 contributes to normaladhesion and migration in untransformed human mammary epithelial cells (HMEC). We alsodemonstrate that p21 inactivation in HMEC suppresses focal adhesion and stress fiber assembly. p21depletion is also associated with inactivation of Rho GTPase and activation of the F-actin severingfactor cofilin. In addition, p21 silencing provokes microtubule hypoacetylation associated withincreased dynamic instability. We find that forced microtubule stabilization by HDAC6 inhibitionpartially restore cell spreading and focal adhesion in p21-depleted cells. Collectively, our data showthat regulation of cytoskeletal dynamics by p21 is required for adhesion control in untransformedhuman epithelial cells.
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Submitted on : Friday, April 5, 2013 - 4:32:16 PM
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  • HAL Id : tel-00808566, version 1



Benjamin Bouchet. Nouvelles fonctions de p21Cip1 dans la dynamique cytosquelettique des cellules épithéliales mammaires humaines. Sciences agricoles. Université Claude Bernard - Lyon I, 2010. Français. ⟨NNT : 2010LYO10056⟩. ⟨tel-00808566⟩



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