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J. Biol. Chem., Vol. 278, Issue 30, 27362-27371, July 25, 2003

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Tumor Suppressor p53 and Its Homologue p73 Affect Cell Migration^*,

Anna A. Sablina  , Peter M. Chumakov  ¶ || ** and Boris P. Kopnin  || 

From the Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, Ohio 44195, Institute of Carcinogenesis, Russian Cancer Research Center, Moscow, Russia 115478, and ^¶Engelhardt Institute of Molecular Biology, Moscow, Russia 119991

The p53 tumor suppressor plays a central role in the negative control of growth and survival of abnormal cells. Previously we demonstrated that in addition to these functions, p53 expression affects cell morphology and lamellar activity of the cell edge (Alexandrova, A., Ivanov, A., Chumakov, P. M., Kopnin, P. B., and Vasiliev, J. M. (2000) Oncogene 19, 5826–5830). In the present work we studied the effects of p53 and its homologue p73 on cell migration. We found that loss of p53 function correlated with decreased cell migration that was analyzed by in vitro wound closure test and Boyden chamber assay. The decreased motility of p53-deficient cells was observed in different cell contexts: human foreskin fibroblasts (BJ), human colon and lung carcinoma cell lines (HCT116 and H1299, respectively), as well as mouse normal fibroblasts from lung and spleen, peritoneal macrophages, and keratinocytes. On the other hand, overexpression of the p53 family member p73 stimulated cell migration. Changes in cell migration correlated directly with transcription activation induced by p53 or p73. Noteworthy, p53 modulated cell motility in the absence of stress. The effect of p53 and p73 on cell migration was mediated through the activity of the phosphatidylinositol 3-kinase/Rac1 pathway. This p53/p73 function was mainly associated with some modulation of intracellular signaling rather than with stimulation of production of secreted motogenic factors. The identified novel activity of the p53 family members might be involved in regulation of embryogenesis, wound healing, or inflammatory response.

Received for publication, January 17, 2003 , and in revised form, May 13, 2003.

^* This work was supported by startup funds from the Lerner Research Institute (to P. M. C.), the International Research Scholars Program of the Howard Hughes Medical Institute (to B. P. K.), and the Russian Foundation for Basic Research (to A. A. S., P. M. C., and B. P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1-7.

^|| Both senior authors contributed equally to this work.

^** To whom correspondence may be addressed. Tel.: 216-444-9540; E-mail: chumakp{at}ccf.org.

To whom correspondence may be addressed. Tel.: 7-095-324-1739; E-mail: bkopnin{at}yahoo.com.

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