Thursday, May 26, 2022
5/26/2022
The human T-cell leukemia virus type-1 (HTLV-1) transforms CD4+ T-lymphocytes and causes adult T-cell leukemia/lymphoma (ATL), an aggressive lymphoproliferative malignancy that responds poorly to most anticancer treatments. The HTLV-1 is a complex oncoretrovirus that encodes several regulatory proteins (Tax, Rex, HBZ, p8I, p12I, p13II, p30II) within a highly conserved 3' nucleotide sequence, known as pX. Whereas numerous studies have focused on the key role of the transactivator protein, Tax, for T-cell immortalization and transformation, much less is known about how the other pX products contribute to viral carcinogenesis and leukemic disease progression. My lab has made significant contributions in this area and provided the first evidence that the HTLV-1 latency-maintenance factor, p30II, cooperates with the host oncoprotein c-Myc and enhances its oncogenic potential through interactions with the TIP60 acetyltransferase, a transcriptional cofactor of both c-Myc and p53. Intriguingly, our preliminary studies have demonstrated that the cooperation between p30II and c-Myc is dependent upon the induction of p53- dependent pro-survival genes. p30II inhibits the TIP60-mediated acetylation of p53 on lysine residue K120, which differentially regulates the expression of p53-dependent apoptotic genes. The p30II protein activates p53 and induces mitochondrial expression of the Tp53-induced glycolysis and apoptosis regulator (TIGAR), a metabolic effector that prevents the intracellular accumulation of c-Myc-induced reactive oxygen species (ROS) and inhibits oncogene-induced cellular senescence. The infectious HTLV-1 mutant proviral clone, ACH.p30II, defective for p30II production, is impaired for TIGAR expression and exhibits a reduced capacity to immortalize primary human PBMCs in vitro. We also found that acute ATL clinical samples exhibit overexpression of TIGAR; and the siRNA-knockdown of TIGAR sensitizes ATL tumor lymphocytes to oncogene-induced ROS and induces cellular senescence. Furthermore, we have identified a structurally- conserved domain within HTLV-1 p30II and the E6 oncoprotein of high-risk human papillomavirus subtype 18 (HPV-18), which similarly activates c-Myc and inhibits p53-dependent apoptosis by destabilizing TIP60. Our preliminary studies demonstrate that 18-E6 induces p53-dependent pro-survival signals which could contribute to the generally more aggressive nature of HPV-18-related cancers. The following Specific Aims are proposed for this R15 project: 1) To determine how the induction of p53-dependent pro-survival signals by p30II promotes oncogene-activation in HTLV-1-infected cells, and 2) to determine if the structurally- conserved domains of HTLV-1 p30II and HPV-18 E6 are functionally interchangeable and modulate p53- dependent gene expression. Our studies have revealed a novel role for p53-dependent pro-survival factors in promoting oncogene-activation by transforming viruses, and suggest that HTLV-1 and HPV-18 may have evolved similar strategies to deregulate host oncogenic signaling during viral carcinogenesis.
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