Transcriptional activation of survivin through the NF-kappaB pathway by human T-cell leukemia virus type I tax.
Survivin, a unique member of the inhibitor of apoptosis protein family, is overexpressed in many cancers and considered to play an important role in oncogenesis. We previously reported the survivin expression profile in ATL, a CD4-positive T-cell malignancy caused by HTLV-I. HTLV-I Tax is thought to play an important role in immortalization of T cells. We have shown also that the expression of Tax protected the mouse T-cell line CTLL-2 against apoptosis induced by deprivation of IL-2 and converted its growth from being IL-2 dependent to being IL-2 independent through the NF-kappaB pathway. In our study, we demonstrate that constitutive expression of survivin was associated with resistance to apoptosis after IL-2 deprivation in Tax-expressing CTLL-2 cells. Transient transfection assays showed that survivin promoter was transactivated by Tax, via the activation of NF-kappaB. Pharmacological NF-kappaB inhibition resulted in suppression of survivin expression and caused apoptosis of Tax-expressing CTLL-2 cells. Our findings suggest that activated NF-kappaB signaling contributes directly to malignant progression of ATL by preventing apoptosis, acting through the prosurvival protein survivin.
Kawakami
Hirochika
H
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Tomita
Mariko
M
Matsuda
Takehiro
T
Ohta
Takao
T
Tanaka
Yuetsu
Y
Fujii
Masahiro
M
Hatano
Masahiko
M
Tokuhisa
Takeshi
T
Mori
Naoki
N
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015973:Gene Expression Regulation, Leukemic; D016356:Gene Products, tax / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D000077022:Survivin; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D016356:Gene Products, tax; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000077022:Survivin