Regulation of HTLV-I oncoprotein Tax by PDLIM2

摘要: Human T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult (ATL). Its encoded oncoprotein Tax plays key roles in HTLV-I-mediated cell transformation and pathogenesis. Although mechanisms by which HTLV-I deregulates cellular signaling for oncogenesis have been extensively studied, how itself regulated remains largely unknown. Here we showed that PDZ-LIM domain-containing protein 2 (PDLIM2, SLIM or Mystique) negatively promoting poly-ubiquitination proteasomal degradation Tax, so to suppress Tax-mediated activation, both vitro animal. To further define molecular determinant responsible PDLIM2 mediated suppression, characterized a putative a-helix motif at amino acids 236-254 was crucial interaction between Tax. with selective disruption this short helix lost tumor suppression function failed altering subcellular distribution as well degradation. Additionally, expression down-regulated HTLV-I-transformed T cells primary ATL samples, re-introduction reversed tumorigenicity malignant cells. The evidence indicated counterbalance might determine outcome infection. Meanwhile, those cells, found DNA methyltransferases (DNMT) 1 3b but not 3a were over-expressed, suggesting involvement methylation repression. Consistently, hypomethylating 5-aza-2'-deoxycytidine (5-aza-dC) restored induced death these Our studies provided important insights into leukemogenicity, long latency cancer heath disparities. Given efficient antitumor activity no obvious toxicity 5-aza-dC, our also suggest potential therapeutic approaches ATL, disease poor treatments.