Activation of the Gene, Coding for the Catalytic Subunit of the Cyclin-Dependent Kinase (CDK)-Activating Kinase (CAK) and General Transcription Factor II H, by the Trans-Activator Protein Tax of Human T-Cell Leukemia Virus Type-1

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2024 Aug 29

PMID 39202439

Authors

Mashiro Shirasawa

Rinka Nakajima

Yaxuan Zhou

Lin Zhao

Mariana Fikriyanti

Ritsuko Iwanaga

Andrew P Bradford

Kenta Kurayoshi

Keigo Araki

Kiyoshi Ohtani

Affiliations

Soon will be listed here.

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The trans-activator protein Tax of HTLV-1 plays crucial roles in leukemogenesis by promoting proliferation of virus-infected cells through activation of growth-promoting genes. However, critical target genes are yet to be elucidated. We show here that Tax activates the gene coding for cyclin-dependent kinase 7 (CDK7), the essential component of both CDK-activating kinase (CAK) and general transcription factor TFIIH. CAK and TFIIH play essential roles in cell cycle progression and transcription by activating CDKs and facilitating transcriptional initiation, respectively. Tax induced gene expression not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs) along with increased protein expression. Tax stimulated phosphorylation of CDK2 and RNA polymerase II at sites reported to be mediated by CDK7. Tax activated the CDK7 promoter through the NF-κB pathway, which mainly mediates cell growth promotion by Tax. Knockdown of CDK7 expression reduced Tax-mediated induction of target gene expression and cell cycle progression. These results suggest that the gene is a crucial target of Tax-mediated trans-activation to promote cell proliferation by activating CDKs and transcription.

References

Uchiyama T . Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol. 1997; 15:15-37. DOI: 10.1146/annurev.immunol.15.1.15. View

Minowada J, Onuma T, Moore G . Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocytes. J Natl Cancer Inst. 1972; 49(3):891-5. View

Kitamura H, Ozono E, Iwanaga R, Bradford A, Okuno J, Shimizu E . Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts. Genes Cells. 2015; 20(9):739-57. DOI: 10.1111/gtc.12268. View

Matsumoto K, Shibata H, Fujisawa J, Inoue H, HAKURA A, Tsukahara T . Human T-cell leukemia virus type 1 Tax protein transforms rat fibroblasts via two distinct pathways. J Virol. 1997; 71(6):4445-51. PMC: 191663. DOI: 10.1128/JVI.71.6.4445-4451.1997. View

Vervoort S, Devlin J, Kwiatkowski N, Teng M, Gray N, Johnstone R . Targeting transcription cycles in cancer. Nat Rev Cancer. 2021; 22(1):5-24. DOI: 10.1038/s41568-021-00411-8. View

Ernzen K, Panfil A . Regulation of HTLV-1 transformation. Biosci Rep. 2022; 42(3). PMC: 8919135. DOI: 10.1042/BSR20211921. View

Huang Y, Ohtani K, Iwanaga R, Matsumura Y, Nakamura M . Direct trans-activation of the human cyclin D2 gene by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene. 2001; 20(9):1094-102. DOI: 10.1038/sj.onc.1204198. View

Martin F, Taylor G, Jacobson S . Inflammatory manifestations of HTLV-1 and their therapeutic options. Expert Rev Clin Immunol. 2014; 10(11):1531-46. DOI: 10.1586/1744666X.2014.966690. View

Giam C, Semmes O . HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ. Viruses. 2016; 8(6). PMC: 4926181. DOI: 10.3390/v8060161. View

10.

Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A . HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986; 1(8488):1031-2. DOI: 10.1016/s0140-6736(86)91298-5. View

11.

Akagi T, Ono H, Shimotohno K . Characterization of T cells immortalized by Tax1 of human T-cell leukemia virus type 1. Blood. 1995; 86(11):4243-9. View

12.

Kaplan J, Tilton J, PETERSON Jr W . Identification of T cell lymphoma tumor antigens on human T cell lines. Am J Hematol. 1976; 1(2):219-23. DOI: 10.1002/ajh.2830010206. View

13.

Rahl P, Lin C, Seila A, Flynn R, McCuine S, Burge C . c-Myc regulates transcriptional pause release. Cell. 2010; 141(3):432-45. PMC: 2864022. DOI: 10.1016/j.cell.2010.03.030. View

14.

Tanaka A, Takahashi C, Yamaoka S, Nosaka T, Maki M, Hatanaka M . Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A. 1990; 87(3):1071-5. PMC: 53412. DOI: 10.1073/pnas.87.3.1071. View

15.

Harhaj E, Giam C . NF-κB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma. FEBS J. 2018; 285(18):3324-3336. PMC: 6750271. DOI: 10.1111/febs.14492. View

16.

Neuveut C, Low K, Maldarelli F, Schmitt I, Majone F, Grassmann R . Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of cyclin D-cdk and p110Rb. Mol Cell Biol. 1998; 18(6):3620-32. PMC: 108944. DOI: 10.1128/MCB.18.6.3620. View

17.

Gessain A, Barin F, Vernant J, Gout O, Maurs L, Calender A . Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985; 2(8452):407-10. DOI: 10.1016/s0140-6736(85)92734-5. View

18.

Yee A, Nichols M, Wu L, Hall F, Kobayashi R, Xiong Y . Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor. Cancer Res. 1995; 55(24):6058-62. View

19.

Iwanaga R, Ohtani K, Hayashi T, Nakamura M . Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene. 2001; 20(17):2055-67. DOI: 10.1038/sj.onc.1204304. View

20.

Iwanaga R, Ozono E, Fujisawa J, Ikeda M, Okamura N, Huang Y . Activation of the cyclin D2 and cdk6 genes through NF-kappaB is critical for cell-cycle progression induced by HTLV-I Tax. Oncogene. 2008; 27(42):5635-42. DOI: 10.1038/onc.2008.174. View