The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis

Abstract

In normal cells, aberrant oncogene expression leads to the accumulation of cytotoxic metabolites, including reactive oxygen species (ROS), which can cause oxidative DNA-damage and apoptosis as an intrinsic barrier against neoplastic disease. The c-Myc oncoprotein is overexpressed in many lymphoid cancers due to c-myc gene amplification and/or 8q24 chromosomal translocations. Intriguingly, p53 is a downstream target of c-Myc and hematological malignancies, such as adult T-cell leukemia/lymphoma (ATL), frequently contain wildtype p53 and c-Myc overexpression. We therefore hypothesized that p53-regulated pro-survival signals may thwart the cell's metabolic anticancer defenses to support oncogene-activation in lymphoid cancers. Here we show that the Tp53-induced glycolysis and apoptosis regulator (TIGAR) promotes c-myc oncogene-activation by the human T-cell leukemia virus type-1 (HTLV-1) latency-maintenance factor p30, associated with c-Myc deregulation in ATL clinical isolates. TIGAR prevents the intracellular accumulation of c-Myc-induced ROS and inhibits oncogene-induced cellular senescence in ATL, acute lymphoblastic leukemia, and multiple myeloma cells with elevated c-Myc expression. Our results allude to a pivotal role for p53-regulated antioxidant signals as mediators of c-Myc oncogenic functions in viral and non-viral lymphoid tumors.

The human T-cell leukemia virus type-1 tax oncoprotein dissociates NF-κB p65RelA-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability

“…The expression of Stathmin is negatively regulated by p53/HDAC1/ mSin3a repressor complexes (Murphy et al, 1999;Ahn et al, 1999), and our studies have demonstrated that the viral latency protein p30 II activates p53 (Romeo et al, 2018) and represses Stathmin/Op-18 (Fig. 1C, D, 4A, and 4B).…”

“…1B shows the sites of amino acid substitution mutations within Tax that impair CREB/ATF-dependent (M47: L319R; L320R; Smith and Greene, 1990) or NF-κB-dependent (M22: T130A; L131S; Smith and Greene, 1990, and G148V;Yamaoka et al, 1996) transactivation. As we have recently shown that the p30 II protein activates p53 and inhibits TIP60-mediated K120-acetylation of p53 (Romeo et al, 2018), we tested whether p30 II might inhibit the expression of Stathmin/Op-18 (as a result of its negative regulation by p53-containing repressor complexes; Murphy et al, 1999;Ahn et al, 1999). Indeed, the results in Fig.…”

“…wildtype (wt) or ACH. p30 II mutant provirus, defective for p30 II production (Hutchison et al, 2018;Bartoe et al, 2000;Romeo et al, 2018;Kimata et al, 1994;Robek et al, 1998), were cotransfected with 0.25 μg of a tk-renillaluciferase plasmid and increasing amounts (0.1, 0.25, 0.5, and 0.75 μg) of an E-Selectin promoter-firefly-luciferase (A) or HIV-1 κB-LTR (ΔTAR)-firefly-luciferase reporter plasmid (B). Dual luciferase assays were carried out and the relative NF-κB-dependent firefly-luciferase activities were quantified and normalized for equivalent renilla-luciferase levels.…”

“…We recently demonstrated in Hutchison et al (2018) that the HTLV-1 latency-maintenance factor p30 II (Nicot et al, 2004;Younis et al, 2004;Zhang et al, 2000;Bartoe et al, 2000) inhibits Tax-induced cytotoxicity and cooperates with the viral transactivator to promote oncogenic colony formation in vitro, dependent upon the activation of p53-regulated pro-survival signals, including the TP53-induced glycolysis and apoptosis regulator (TIGAR; Bensaad et al, 2006;Bensaad et al, 2009) which suppresses Tax-induced oxidative stress. p30 II interacts with the MYST-family acetyltransferase TIP60 (Awasthi et al, 2005;Romeo et al, 2015) and inhibits lysine K120acetylation of the p53 protein (Romeo et al, 2018) which differentially regulates the expression of p53-dependent pro-apoptotic genes (Sykes et al, 2006;Tang et al, 2006;Kurash et al, 2008;Dar et al, 2013;Xu et al, 2014). Interestingly, the p53 tumor suppressor is mutated in nearly half of all cancers; however, it is rarely mutated in HTLV-1+ ATLL clinical isolates which frequently contain high levels of wildtype p53 (Zane et al, 2012;b Pise-Masison et al, 1998;Tabakin-Fix et al, 2006;Mengle-Gaw and Rabbitts, 1987), suggesting the subversion of p53-regulated target genes may contribute to viral carcinogenesis (Hutchison et al, 2018;Romeo et al, 2018).…”

“…p30 II interacts with the MYST-family acetyltransferase TIP60 (Awasthi et al, 2005;Romeo et al, 2015) and inhibits lysine K120acetylation of the p53 protein (Romeo et al, 2018) which differentially regulates the expression of p53-dependent pro-apoptotic genes (Sykes et al, 2006;Tang et al, 2006;Kurash et al, 2008;Dar et al, 2013;Xu et al, 2014). Interestingly, the p53 tumor suppressor is mutated in nearly half of all cancers; however, it is rarely mutated in HTLV-1+ ATLL clinical isolates which frequently contain high levels of wildtype p53 (Zane et al, 2012;b Pise-Masison et al, 1998;Tabakin-Fix et al, 2006;Mengle-Gaw and Rabbitts, 1987), suggesting the subversion of p53-regulated target genes may contribute to viral carcinogenesis (Hutchison et al, 2018;Romeo et al, 2018). Although there is currently no commercial antibody available to detect the p30 II protein, the alternatively-spliced pX-orfII-p30 mRNA has been detected by RT-PCR in chronically HTLV-1-infected T-cell-lines, primary uncultured ATLL clinical isolates, and PBMCs from asymptomatic carriers (Princler et al, 2003;Berneman et al, 1992;Koralnik et al, 1992;Ciminale et al, 1992).…”