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J. Biol. Chem., Vol. 282, Issue 45, 32991-32999, November 9, 2007

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Granzyme B-induced Cell Death Involves Induction of p53 Tumor Suppressor Gene and Its Activation in Tumor Target Cells^*

From the INSERM U753, Laboratoire d'Immunologie des Tumeurs Humaines, Interaction Effecteurs Cytotoxiques-Système Tumoral, Institut Gustave Roussy PR1, IFR 54, 94805 Villejuif Cedex, France

In this study we investigated the involvement of p53 in cytotoxic T-lymphocyte (CTL)-induced tumor target cell killing mediated by the perforin/granzymes pathway. For this purpose we used a human CTL clone (LT12) that kills its autologous melanoma target cells (T1), harboring a wild type p53. We demonstrated initially that LT12 kills its T1 target in a perforin/granzymes-dependent manner. Confocal microscopy and Western blot analysis indicated that conjugate formed between LT12 and T1 resulted in rapid cytoplasmic accumulation of p53 and its activation in T1 target cells. Cytotoxic assay using recombinant granzyme B (GrB) showed that this serine protease is the predominant factor inducing such accumulation. Furthermore, RNA interference-mediated lowering of the p53 protein in T1 cells or pifithrin--induced p53-specific inhibition activity significantly decreased CTL-induced target killing mediated by CTL or recombinant GrB. This emphasizes that p53 is an important determinant in granzyme B-induced apoptosis. Our data show furthermore that when T1 cells were treated with streptolysin-O/granzyme B, specific phosphorylation of p53 at Ser-15 and Ser-37 residues was observed subsequent to the activation of the stress kinases ataxia telangiectasia mutated (ATM) and p38K. Treatment of T1 cells with pifithrin- resulted in inhibition of p53 phosphorylation at these residues and in a significant decrease in GrB-induced apoptotic T1 cell death. Furthermore, small interference RNAs targeting p53 was also accompanied by an inhibition of streptolysin-O/granzyme B-induced apoptotic T1 cell death. The present study supports p53 induction after CTL-induced stress in target cells. These findings provide new insight into a potential role of p53 as a component involved in the dynamic regulation of the major pathway of CTL-mediated cell death and may have therapeutic implications.

Received for publication, June 28, 2007 , and in revised form, September 4, 2007.

^* This work was supported by grants from the INSERM, Association pour la Recherche contre le Cancer Grants 4744, 3501, and 3922, Ligue contre le Cancer Grant SR2005-430 (comité des Hauts de Seine), and by the Cancéropole Ile-de-France and the Institut National du Cancer. 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 supplemental Figs. S1–S3.

¹ These authors contributed equally to this work.

² Supported by a fellowship from La Ligue contre le Cancer.

³ Supported by a fellowship from L'Association pour la Recherche contre le Cancer and La Société Française du Cancer.

⁴ To whom correspondence should be addressed: Laboratoire d'Immunologie des Tumeurs Humaines, Interaction Effecteurs Cytotoxiques-Système Tumoral, U753 INSERM, Institut Gustave Roussy, 39 rue Camille Desmoulins F-94805 Villejuif Cedex, France. Tel.: 33-142114547; Fax: 33-142115288; E-mail: chouaib{at}igr.fr.

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