Abstract
BackgroundHuman 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.ResultsUsing 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.ConclusionsOur findings provide new insights into contributions by p53 and Wip1 in the in vivo oncogenesis of Tax-induced tumors in mice.
Highlights
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
The virus belongs to the deltaretrovirus family and is the etiological agent of a highly aggressive neoplastic disease, Adult T-cell Leukemia/Lymphoma (ATLL), and inflammatory diseases including HTLV-1 Associated Myelopathy (HAM)/Tropical Spastic Paraparesis (TSP), uveitis, infective dermatitis and myositis [1,2,3,4,5,6,7,8,9]
Using various genetically altered mice, we show that Tax inactivation of p53 is functionally less stringent than p53 inactivation by genetic mutation, and we report that the cellular Wip1 phosphatase protein collaborates functionally with Tax in inhibiting p53 activity
Summary
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. HTLV-1 encodes a viral oncoprotein, Tax, that functions in transforming virus-infected T-cells into leukemic cells. The virus belongs to the deltaretrovirus family and is the etiological agent of a highly aggressive neoplastic disease, Adult T-cell Leukemia/Lymphoma (ATLL), and inflammatory diseases including HTLV-1 Associated Myelopathy (HAM)/Tropical Spastic Paraparesis (TSP), uveitis, infective dermatitis and myositis [1,2,3,4,5,6,7,8,9]. In transforming a normal T-cell into a leukemic cell, it is believed that Tax must neutralize cellular checkpoints (e.g. p53 and mitotic spindle assembly checkpoint) that act to censor DNA damage [43,44] and aneuploidy [45,46]
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