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Molecular and Cellular Biology, June 2009, p. 3088-3098, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01816-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

p53 Suppresses Src-Induced Podosome and Rosette Formation and Cellular Invasiveness through the Upregulation of Caldesmon{triangledown} ,{dagger}

Utpal K. Mukhopadhyay, Robert Eves, Lilly Jia, Patrick Mooney, and Alan S. Mak*

Department of Biochemistry, Queen's University, Kingston, ON K7L 3N6, Canada

Received 28 November 2008/ Returned for modification 4 January 2009/ Accepted 25 March 2009

The tumor-suppressive role of p53 at the level of tumor initiation is well documented. It has also been shown previously that p53 acts against tumor progression/metastasis. However, its role in modulating cell migration and invasion leading to metastasis is poorly understood. In this study, using vascular smooth muscle cells and NIH 3T3 fibroblast cells, we have shown that p53 potently suppresses Src-induced podosome/rosette formation, extracellular matrix digestion, cell migration, and invasion. The overexpression of exogenous wild-type p53 or the activation of the endogenous p53 function suppresses, while the short hairpin RNA-mediated knockdown of p53 expression or the blocking of its function exacerbates, Src-induced migratory and invasive phenotypes. We have also found that p53 expression and function are downregulated in cells stably transformed with constitutively active Src that exhibit aggressive invasive properties. Lastly, p53 upregulates the expression of caldesmon, an actin-binding protein that has been shown to be an inhibitor of podosome/invadopodium formation. The ability of p53 to suppress Src phenotypes in transformed cells was largely abolished by knocking down caldesmon. This study reports a novel molecular mechanism (caldesmon), as well as a structural basis (podosomes/rosettes), to show how p53 can act as an anti-motility/invasion/metastasis agent.

* Corresponding author. Mailing address: Department of Biochemistry, Queen's University, Kingston, ON K7L 3N6, Canada. Phone: (613) 533-2989. Fax: (613) 533-2497. E-mail: maka{at}queensu.ca

{triangledown} Published ahead of print on 6 April 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2009, p. 3088-3098, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.01816-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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