RRC ID 67652
Author Higuchi M, Takahashi M, Tanaka Y, Fujii M.
Title Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.
Journal Cancer Med
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.
Volume 3(6)
Pages 1605-14
Published 2014-12-1
DOI 10.1002/cam4.329
PMID 25175936
PMC PMC4298387
MeSH Animals Apoptosis / physiology Apoptosis Regulatory Proteins / deficiency Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism* Bcl-2-Like Protein 11 Cell Line, Tumor Cell Transformation, Viral* Down-Regulation Gene Knockdown Techniques Gene Products, tax / genetics Gene Products, tax / metabolism Gene Products, tax / physiology* HEK293 Cells Human T-lymphotropic virus 1 / genetics Human T-lymphotropic virus 1 / metabolism Human T-lymphotropic virus 1 / physiology* Humans Interleukin-2 / deficiency* Jurkat Cells Leukemia-Lymphoma, Adult T-Cell / genetics Leukemia-Lymphoma, Adult T-Cell / metabolism Leukemia-Lymphoma, Adult T-Cell / pathology Leukemia-Lymphoma, Adult T-Cell / virology* Membrane Proteins / deficiency Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Proto-Oncogene Proteins / deficiency Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* T-Lymphocytes / metabolism T-Lymphocytes / pathology T-Lymphocytes / virology*
IF 3.491
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)