Wip1 and p53 contribute to HTLV-1 Tax-induced tumorigenesis
1 Molecular Virology Section, Laboratory of Molecular Microbiology, the National Institutes of Allergy and Infectious Diseases, the National Institutes of Health, Bethesda, Maryland, 20892-0460, USA
2 Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan
3 Department of Medicine, Washington University School of Medicine, Saint-Louis, Missouri, USA
4 Department of Cancer Biology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Retrovirology 2012, 9:114 doi:10.1186/1742-4690-9-114Published: 21 December 2012
Human T-cell Leukemia Virus type 1 (HTLV-1) infects 20 million individuals world-wide and causes Adult T-cell Leukemia/Lymphoma (ATLL), a highly aggressive T-cell cancer. ATLL is refractory to treatment with conventional chemotherapy and fewer than 10% of afflicted individuals survive more than 5 years after diagnosis. HTLV-1 encodes a viral oncoprotein, Tax, that functions in transforming virus-infected T-cells into leukemic cells. All ATLL cases are believed to have reduced p53 activity although only a minority of ATLLs have genetic mutations in their p53 gene. It has been suggested that p53 function is inactivated by the Tax protein.
Using genetically altered mice, we report here that Tax expression does not achieve a functional equivalence of p53 inactivation as that seen with genetic mutation of p53 (i.e. a p53−/− genotype). Thus, we find statistically significant differences in tumorigenesis between Tax+p53+/+versus Tax+p53−/− mice. We also find a role contributed by the cellular Wip1 phosphatase protein in tumor formation in Tax transgenic mice. Notably, Tax+Wip1−/− mice show statistically significant reduced prevalence of tumorigenesis compared to Tax+Wip1+/+ counterparts.
Our findings provide new insights into contributions by p53 and Wip1 in the in vivo oncogenesis of Tax-induced tumors in mice.