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Molecular and Cellular Biology, February 2005, p. 1013-1024, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1013-1024.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Oncoprotein E7 Targets the Promyelocytic Leukemia Protein and Circumvents Cellular Senescence via the Rb and p53 Tumor Suppressor Pathways

Oliver Bischof, Karim Nacerddine, and Anne Dejean*

Nuclear Organisation and Oncogenesis Unit, INSERM U 579, Institut Pasteur, Paris, France

Received 20 February 2004/ Returned for modification 27 April 2004/ Accepted 29 October 2004

Cellular senescence can be triggered by a variety of signals, including loss of telomeric integrity or intense oncogenic signaling, and is considered a potent, natural tumor suppressor mechanism. Previously, it was shown that the promyelocytic leukemia protein (PML) induces cellular senescence when overexpressed in primary human fibroblasts. The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally. To investigate the individual contributions of p53 and Rb to PML-induced senescence, we used oncoproteins E6 and E7 from human papillomaviruses (HPVs), which predominantly target p53 and Rb. We show that E7, but not E6, circumvents PML-induced senescence. Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7. Interaction between E7 and a functional prosenescence complex composed of PML, p53, and CBP perturbs transcriptional activation of p53, thus highlighting a significant effect also on the p53 tumor suppressor pathway. Given the importance of HPV in the pathogenesis of cervical cancer, our results warrant a more detailed analyses of PML in HPV infections.

* Corresponding author. Mailing address: Nuclear Organisation and Oncogenesis Unit, INSERM U579, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 88 86. Fax: 33 1 45 68 89 43. E-mail: adejean{at}pasteur.fr.

Molecular and Cellular Biology, February 2005, p. 1013-1024, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1013-1024.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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