title: HTLV-1 bZIP Factor RNA and Protein Impart Distinct Functions on T-cell Proliferation and Survival.
abstract: Infection of T cells with human T-cell leukemia virus type-1 (HTLV-1) induces clonal proliferation and is closely associated with the onset of adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. Although Tax expression is frequently suppressed in HTLV-1-infected cells, the accessory gene, HTLV-1 bZIP factor (HBZ), is continuously expressed and has been implicated in HTLV-1 pathogenesis. Here, we report that transduction of mouse T cells with specific mutants of HBZ that distinguish between its RNA and protein activity results in differential effects on T-cell proliferation and survival. HBZ RNA increased cell number by attenuating apoptosis, whereas HBZ protein induced apoptosis. However, both HBZ RNA and protein promoted S-phase entry of T cells. We further identified that the first 50 bp of the HBZ coding sequence are required for RNA-mediated cell survival. Transcriptional profiling of T cells expressing wild-type HBZ, RNA, or protein revealed that HBZ RNA is associated with genes involved in cell cycle, proliferation, and survival, while HBZ protein is more closely related to immunological properties of T cells. Specifically, HBZ RNA enhances the promoter activity of survivin, an inhibitor of apoptosis, to upregulate its expression. Inhibition of survivin using YM155 resulted in impaired proliferation of several ATL cell lines as well as a T-cell line expressing HBZ RNA. The distinct functions of HBZ RNA and protein may have several implications for the development of strategies to control the proliferation and survival mechanisms associated with HTLV-1 infection and ATL.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan. Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Mitobe
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan. mmatsuok@virus.kyoto-u.ac.jp jyasunag@virus.kyoto-u.ac.jp.
authors.forename: Jun-ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Furuta
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan. mmatsuok@virus.kyoto-u.ac.jp jyasunag@virus.kyoto-u.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D015967:Gene Expression Regulation, Viral; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009285:Naphthoquinones / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012191:Retroviridae Proteins / Q000235:genetics / Q000502:physiology*; D000077022:Survivin; D013601:T-Lymphocytes / Q000502:physiology / Q000821:virology*; D014158:Transcription, Genetic; D014161:Transduction, Genetic
chemical_list: C107489:BIRC5 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; C117749:Birc5 protein, mouse; C479751:HBZ protein, human T-cell leukemia virus type I; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D012367:RNA, Viral; C039919:RNA, recombinant; D012097:Repressor Proteins; D012191:Retroviridae Proteins; D000077022:Survivin; D012313:RNA; C523798:sepantronium