Downregulation of CDKN1A in adult T-cell leukemia/lymphoma despite overexpression of CDKN1A in human T-lymphotropic virus 1-infected cell lines.
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.
Watanabe
Masaaki
M
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan.
Nakahata
Shingo
S
Hamasaki
Makoto
M
Saito
Yusuke
Y
Kawano
Yohei
Y
Hidaka
Tomonori
T
Yamashita
Kiyoshi
K
Umeki
Kazumi
K
Taki
Tomohiko
T
Taniwaki
Masafumi
M
Okayama
Akihiko
A
Morishita
Kazuhiro
K
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
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
Blood. 1995 Dec 1;86(11):4243-9
7492783
J Infect Dis. 2005 Apr 1;191(7):1140-7
15747250
J Virol. 2008 Dec;82(23):11958-63
18922876
Cancer Res. 2002 Jun 15;62(12):3562-71
12068005
Int J Cancer. 1990 Feb 15;45(2):237-43
2303290
Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-9
6261256
World J Gastroenterol. 2002 Jun;8(3):400-5
12046058
Br J Haematol. 2001 May;113(2):375-82
11380402
Oncogene. 1999 Feb 11;18(6):1341-9
10022816
Clin Cancer Res. 2004 Jun 1;10(11):3815-24
15173090
Retrovirology. 2004 Apr 13;1:6
15169570
Oncogene. 1999 Apr 15;18(15):2441-50
10229195
Mol Cell Biol. 2003 Jun;23(12):4056-65
12773551
AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1695-700
11080812
Oncogene. 2008 Jun 5;27(25):3615-23
18223691
Retrovirology. 2005 Oct 22;2:64
16242045
Int J Cancer. 2004 Apr 20;109(4):559-67
14991578
Nat Rev Cancer. 2007 Apr;7(4):270-80
17384582
Blood. 2008 Jul 15;112(2):383-93
18467597
J Virol. 2000 Aug;74(16):7270-83
10906181
Nat Cell Biol. 2001 Mar;3(3):245-52
11231573
J Biol Chem. 2006 Mar 31;281(13):8927-38
16436385
Breast Cancer Res. 2003;5(6):R242-9
14580260
Nat Med. 2002 Oct;8(10):1145-52
12244301
Nat Med. 2002 Oct;8(10):1136-44
12244303
Blood. 2005 Feb 1;105(3):1204-13
15471956
Oncogene. 2005 Sep 5;24(39):6058-68
16155612
Cancer Res. 2000 Jan 15;60(2):262-5
10667572
Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618-22
6304725
J Virol. 2002 Sep;76(18):9389-97
12186921
Blood. 2002 Apr 1;99(7):2291-6
11895758
Anal Biochem. 1995 Mar 20;226(1):161-6
7785768
J Biol Chem. 2009 Jan 30;284(5):2680-2689
19047050
Oncogene. 2003 Sep 29;22(42):6489-96
14528273
Curr Treat Options Oncol. 2001 Aug;2(4):291-300
12057109
J Virol. 2005 Nov;79(22):14069-78
16254341
Nat Med. 2002 Oct;8(10):1153-60
12244302
Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031-5
6979048