Loss of interleukin-2-dependency in HTLV-I-infected T cells on gene silencing of thioredoxin-binding protein-2.
The transition from interleukin-2 (IL-2)-dependent to IL-2-independent growth is considered one of the key steps in the transformation of human T-cell leukemia virus type-I (HTLV-I)-infected T cells. The expression of thioredoxin-binding protein-2 (TBP-2) is lost during the transition of HTLV-I-infected T-cell lines. Here, we analysed the mechanism of loss of TBP-2 expression and the role of TBP-2 in IL-2-dependent growth in the in vitro model to investigate multistep transformation of HTLV-I. CpGs in the TBP-2 gene are methylated in IL-2-independent but not in IL-2-dependent cells. Sequential treatment with 5-aza-2'-deoxycytidine and a histone deacetylase inhibitor augmented histone acetylation and TBP-2 expression, suggesting that loss of TBP-2 expression is due to DNA methylation and histone deacetylation. In IL-2-dependent cells, a basal level of TBP-2 expression was maintained by IL-2 associated with cellular growth, whereas TBP-2 expression was upregulated on deprivation of IL-2 associated with growth suppression. Overexpression of TBP-2 in IL-2-independent cells suppressed the growth and partially restored responsiveness to IL-2. Knockdown of TBP-2 caused the IL-2-dependent cells to show partial growth without IL-2. These results suggested that epigenetic silencing of the TBP-2 gene results in a loss of responsiveness to IL-2, contributing to uncontrolled IL-2-independent growth in HTLV-I-infected T-cell lines.
Ahsan
M K
MK
Department of Biological Responses, Institute for Virus Research, Kyoto University, Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, Japan.
Masutani
H
H
Yamaguchi
Y
Y
Kim
Y-C
YC
Nosaka
K
K
Matsuoka
M
M
Nishinaka
Y
Y
Maeda
M
M
Yodoi
J
J
D000107:Acetylation; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000077337:Vorinostat
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007376:Interleukin-2; D012333:RNA, Messenger; C486715:TXNIP protein, human; D013879:Thioredoxins; D000077337:Vorinostat; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine