Oncotarget

Priority Research Papers:

p53 elevation in human cells halt SV40 infection by inhibiting T-ag expression

Nir Drayman _, Orly Ben-nun-Shaul, Veronika Butin-Israeli, Rohit Srivastava, Ariel M. Rubinstein, Caroline S. Mock, Ela Elyada, Yinon Ben-Neriah, Galit Lahav and Ariella Oppenheim

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Oncotarget. 2016; 7:52643-52660. https://doi.org/10.18632/oncotarget.10769

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Abstract

Nir Drayman1,4, Orly Ben-nun-Shaul1, Veronika Butin-Israeli1, Rohit Srivastava1, Ariel M. Rubinstein1, Caroline S. Mock2, Ela Elyada3, Yinon Ben-Neriah3, Galit Lahav2 and Ariella Oppenheim1

1 Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel

2 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

3 The Lautenberg Center for Immunology and Cancer Research, Hebrew University Faculty of Medicine, Jerusalem, Israel

4 Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel

Correspondence to:

Ariella Oppenheim, email:

Galit Lahav, email:

Nir Drayman, email:

Keywords: p53, SV40, large T-antigen, Sp1, host defense

Received: July 06, 2016 Accepted: July 14, 2016 Published: July 21, 2016

Abstract

SV40 large T-antigen (T-ag) has been known for decades to inactivate the tumor suppressor p53 by sequestration and additional mechanisms. Our present study revealed that the struggle between p53 and T-ag begins very early in the infection cycle. We found that p53 is activated early after SV40 infection and defends the host against the infection. Using live cell imaging and single cell analyses we found that p53 dynamics are variable among individual cells, with only a subset of cells activating p53 immediately after SV40 infection. This cell-to-cell variabilty had clear consequences on the outcome of the infection. None of the cells with elevated p53 at the beginning of the infection proceeded to express T-ag, suggesting a p53-dependent decision between abortive and productive infection. In addition, we show that artificial elevation of p53 levels prior to the infection reduces infection efficiency, supporting a role for p53 in defending against SV40. We further found that the p53-mediated host defense mechanism against SV40 is not facilitated by apoptosis nor via interferon-stimulated genes. Instead p53 binds to the viral DNA at the T-ag promoter region, prevents its transcriptional activation by Sp1, and halts the progress of the infection. These findings shed new light on the long studied struggle between SV40 T-ag and p53, as developed during virus-host coevolution. Our studies indicate that the fate of SV40 infection is determined as soon as the viral DNA enters the nucleus, before the onset of viral gene expression.


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