Transcriptional and post-transcriptional gene regulation of HTLV-1.
Adult T-cell leukemia (ATL) is an aggressive hematologic malignancy caused by human T-cell leukemia virus type I (HTLV-1). Tax, encoded by the HTLV-1 pX region, has been recognized by its pleiotropic actions to play a critical role in leukemogenesis. Three highly conserved 21-bp repeat elements located within the long terminal repeat, commonly referred to as Tax-responsive element 1 (TRE-1), are critical to Tax-mediated viral transcriptional activation through complex interaction with cyclic AMP-responsive element binding protein (CREB), CBP/p300 and PCAF. Tax has also been shown to activate transcription from a number of critical cellular genes through the NF-kappaB and serum-responsive factor pathways. Tax transactivation has been attributed to the protein's interaction with transcription factors, chromatin remodeling complexes, cell cycle and repair genes. In this review, we will discuss some of the latest findings on this fascinating viral activator and highlight its regulation of cellular factors including CREB, p300/CBP and their effect on RNA polymerase II and chromatin remodeling, as well as its role in cytoplasmic and nuclear function. We will highlight the possible contribution of each factor, discuss Tax's critical peptide domains and highlight its post-transcriptional modifications. It is quite obvious that, collectively, Tax's effects on a wide variety of cellular targets cooperate in promoting cell proliferation and leukemogenesis. In addition, the post-transcriptional effects of Rex play an important role in virus replication. Understanding these interactions at a molecular level will facilitate the targeted development of drugs to effectively inhibit or treat ATL.
Kashanchi
Fatah
F
Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, 2300 Eye St, NW, Ross Hall, Washington, DC, USA. bcmfxk@gwumc.eduz
Brady
John N
JN
D015967:Gene Expression Regulation, Viral; D016370:Gene Products, rex / Q000235:genetics; D016356:Gene Products, tax / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics
D016370:Gene Products, rex; D016356:Gene Products, tax; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins