title: Downregulation of CDKN1A in adult T-cell leukemia/lymphoma despite overexpression of CDKN1A in human T-lymphotropic virus 1-infected cell lines.
abstract: Human T-lymphotropic virus 1 (HTLV-1) causes an aggressive malignancy of T lymphocytes called adult T-cell leukemia/lymphoma (ATLL), and expression of HTLV-1 Tax influences cell survival, proliferation, and genomic stability in the infected T lymphocytes. Cyclin-dependent kinase inhibitor 1A (CDKN1A/p21(waf1/Cip1)) is upregulated by Tax, without perturbation of cell cycle control. During an analysis of the gene expression profiles of ATLL cells, we found very low expression of CDKN1A in ATLL-derived cell lines and ATLL cells from patient samples, and epigenetic abnormalities including promoter methylation are one of the mechanisms for the low CDKN1A expression in ATLL cells. Three HTLV-1-infected cell lines showed high levels of expression of both CDKN1A and Tax, but expression of CDKN1A was detected in only two of six ATLL-derived cell lines. In both the HTLV-1-infected and ATLL cell lines, we found that activated Akt phosphorylates CDKN1A at threonine 145 (T145), leading to cytoplasmic localization of CDKNIA. In HTLV-1-infected cell lines, cytoplasmic CDKN1A did not inhibit the cell cycle after UV irradiation; however, following treatment with LY294002, a PI3K inhibitor, CDKN1A was dephosphorylated and relocalized to the nucleus, resulting in suppression of the cell cycle. In the ATLL cell lines, treatment with LY294002 did not inhibit the cell cycle but induced apoptosis with the cytoplasmic localization. Therefore, the low CDKN1A expression in ATLL cells may be a key player in ATLL leukemogenesis, and the abnormal genomic methylation may influence the expression of not only HTLV-1 Tax but also CDKN1A during long-term development of ATLL from the HTLV-1-infected T lymphocytes.
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakahata
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamasaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Saito
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hidaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamashita
authors.forename: Kazumi
authors.initials: K
authors.lastname: Umeki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okayama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morishita
mesh_terms: D000328:Adult; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D046228:Microarray Analysis; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016356:Gene Products, tax; C514970:tax protein, Human T-lymphotrophic virus 1; D051057:Proto-Oncogene Proteins c-akt
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