HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes.
Human T-cell leukemia virus type I (HTLV-I)-associated malignancies are seen in a small percentage of infected persons. Although in vitro immortalization by HTLV-I virus is very efficient, we report that Tax has poor oncogenic activity in human primary T cells and that immortalization by Tax is rare. Sustained telomerase activity represents one of the oncogenic steps required for Tax-mediated immortalization. Tax expression was required for the growth of primary T cells, but was not sufficient to propel T cells into cell cycle in the absence of exogenous interleukin-2 (IL-2). Tax was sufficient to activate the phosphoinositide-3 kinase (PI3K)/Akt pathway as shown by down regulation of Src homology phosphatase-1 and increased phosphorylation of Akt. We also found disruption of putative tumor suppressors IL-16 and translocated promoter region (TPR) in Tax-immortalized and HTLV-I-transformed cell lines. Our results confirmed previous observations that Tax activates the anaphase-promoting complex. However, Tax did not affect the mitotic spindle checkpoint, which was also functional in HTLV-I-transformed cells. These data provide a better understanding of Tax functions in human T cells, and highlight the limitations of Tax, suggesting that other viral proteins are key to T-cell transformation and development of adult T-cell leukemia.
Bellon
Marcia
M
University of Kansas Medical Center, Department of Pathology and Laboratory Medicine, Center for Viral Oncology, KU Cancer Center, Kansas City, KS 66160, USA.
Baydoun
Hicham H
HH
Yao
Yuan
Y
Nicot
Christophe
C
D000328:Adult; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000502:physiology*; D016922:Cellular Senescence / Q000502:physiology; D002869:Chromosome Aberrations; D016356:Gene Products, tax / Q000235:genetics*; D042822:Genomic Instability / Q000502:physiology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D016399:Lymphoma, T-Cell / Q000473:pathology / Q000821:virology*; D013601:T-Lymphocytes / Q000473:pathology / Q000821:virology*; D016615:Telomere / Q000502:physiology
D016356:Gene Products, tax; D007376:Interleukin-2; C514970:tax protein, Human T-lymphotrophic virus 1