Activation of cyclin D1 and D2 promoters by human T-cell leukemia virus type I tax protein is associated with IL-2-independent growth of T cells.
Our aim was to examine the involvement of G(1) cell-cycle regulators in cell growth dysregulation induced by HTLV-I. Compared to uninfected cells, higher expression levels of cyclin D1 and D2 mRNA were detected in HTLV-I-infected T-cell lines, which were at least in part mediated by the viral transforming protein Tax since Tax activated both cyclin D1 and D2 promoters in the human T-cell line Jurkat. A Tax mutant that did not activate NF-kappaB failed to activate cyclin D1 and D2 promoters. Inhibitors of NF-kappaB (dominant negative IkappaBs mutants) suppressed Tax-dependent activation of cyclin D1 and D2 promoters, indicating that Tax-induced activation was mediated by NF-kappaB. Wild-type and mutant Tax capable of activating NF-kappaB, but not Tax mutant incapable of activating NF-kappaB, converted cell growth of a T-cell line from being IL-2-dependent to being IL-2-independent; and this conversion was associated with IL-2-independent induction of cyclins D1 and D2. Our data suggest that induction of cyclins D1 and D2 by Tax is involved in IL-2-independent cell-cycle progression as well as IL-2-independent transformation of primary human T cells by HTLV-I. High expression levels of cyclin D1 and D2 mRNAs were also detected in some patients with ATL. Our findings link HTLV-I infection to changes in cellular D-type cyclin gene expression, transformation of T cells and subsequent development of T-cell leukemia.
Mori
Naoki
N
Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
Fujii
Masahiro
M
Hinz
Michael
M
Nakayama
Katsushi
K
Yamada
Yasuaki
Y
Ikeda
Shuichi
S
Yamasaki
Yoshihiro
Y
Kashanchi
Fatah
F
Tanaka
Yuetsu
Y
Tomonaga
Masao
M
Yamamoto
Naoki
N
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D019938:Cyclin D1 / Q000235:genetics*; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D007700:Kinetics; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C080336:CCND2 protein, human; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D016356:Gene Products, tax; D007376:Interleukin-2; D016328:NF-kappa B; D012333:RNA, Messenger; D019938:Cyclin D1