This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Garner, E. Articles by Raj, K. Search for Related Content PubMed PubMed Citation Articles by Garner, E. Articles by Raj, K.

Cells with Defective p53-p21-pRb Pathway Are Susceptible to Apoptosis Induced by p84N5 via Caspase-6

¹ Department of Virology, National Institute for Medical Research, London, United Kingdom; ² Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts; ³ Institute of Biochemistry, University of Lausanne; and ⁴ Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland

Requests for reprints: Kenneth Raj, Department of Virology, National Institute for Medical Research, The Ridge Way, Mill Hill, London, NW7 1AA United Kingdom. Phone: 44-20-8816-2191; Fax: 44-20-8906-4477; E-mail: kraj{at}nimr.mrc.ac.uk.

Adeno-associated virus (AAV) infection triggers a DNA damage response in the cell. This response is not induced by viral proteins but by virtue of the structure of AAV ssDNA being recognized by the cell as damaged DNA. The consequence of this is the killing of cells lacking p53 activity. We have observed that cells that lack p21 or pRb activity are also sensitive to AAV-induced cell death. We report that cells respond to AAV infection by activating two DNA damage signaling cascades. The first activates the p84N5 protein, which in turn activates caspase-6, leading to cell death. The second cascade activates the p53-21-pRb pathway, which inhibits activation of the p84N5 protein and thus prevents cell death. The result of the antagonistic interaction between these two pathways is that cells that do not exhibit functional p53-p21-pRb signaling undergo apoptosis as a consequence of AAV infection. Cells with a functional p53-21-pRb pathway are refractory to AAV-induced cell death. These results show that p53, although a proapoptotic protein, together with pRb and p21 proteins, is a member of an antiapoptotic cellular mechanism. As such, these experiments reveal features that may be exploited to specifically kill cells that lack the p53-p21-pRb pathway, such as cancer cells. The use of AAV to expose these subtle characteristics of intracellular signaling further highlights the advantages of using viruses as precision tools with which to address questions of cell biology. [Cancer Res 2007;67(16):7631–7]

This article has been cited by other articles:

				M. Fragkos, J. Jurvansuu, and P. Beard H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway Mol. Cell. Biol., May 15, 2009; 29(10): 2828 - 2840. [Abstract] [Full Text] [PDF]