title: p53 elevation in human cells halt SV40 infection by inhibiting T-ag expression.
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.
authors.affiliation: Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel.|Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Drayman
authors.affiliation: Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Ben-Nun-Shaul
authors.affiliation: Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Veronika
authors.initials: V
authors.lastname: Butin-Israeli
authors.affiliation: Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Rohit
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Rubinstein
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Mock
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Ela
authors.initials: E
authors.lastname: Elyada
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, Hebrew University Faculty of Medicine, Jerusalem, Israel.
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Galit
authors.initials: G
authors.lastname: Lahav
authors.affiliation: Department of Hematology, Hebrew University Faculty of Medicine and Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Ariella
authors.initials: A
authors.lastname: Oppenheim
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D013539:Simian virus 40 / Q000235:genetics* / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D059008:Time-Lapse Imaging / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53
keywords: SV40; Sp1; host defense; large T-antigen; p53