title: Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.
abstract: Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion-induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.
authors.affiliation: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Higuchi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000172:deficiency*; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016356:Gene Products, tax; D007376:Interleukin-2; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C514970:tax protein, Human T-lymphotrophic virus 1
keywords: ATL; BIM protein; ERK MAP kinases; HTLV-1 Tax genes; apoptosis