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: Masaya Higuchi, Masahiko Takahashi, Yuetsu Tanaka, Masahiro Fujii
• Journal: Cancer medicine (Cancer Med) Vol. 3 Issue 6 Pg. 1605-14 (Dec 2014) ISSN: 2045-7634 [Electronic] United States
• PMID: 25175936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Gene Products, tax
• Interleukin-2
• Membrane Proteins
• Proto-Oncogene Proteins
• tax protein, Human T-lymphotrophic virus 1

Topics

• Animals
• Apoptosis (physiology)
• Apoptosis Regulatory Proteins (deficiency, genetics, metabolism)
• Bcl-2-Like Protein 11
• Cell Line, Tumor
• Cell Transformation, Viral
• Down-Regulation
• Gene Knockdown Techniques
• Gene Products, tax (genetics, metabolism, physiology)
• HEK293 Cells
• Human T-lymphotropic virus 1 (genetics, metabolism, physiology)
• Humans
• Interleukin-2 (deficiency)
• Jurkat Cells
• Leukemia-Lymphoma, Adult T-Cell (genetics, metabolism, pathology, virology)
• Membrane Proteins (deficiency, genetics, metabolism)
• Mice
• Proto-Oncogene Proteins (deficiency, genetics, metabolism)
• T-Lymphocytes (metabolism, pathology, virology)