Complex cell cycle abnormalities caused by human T-Lymphotropic virus type 1 tax

Liangpeng Yang, Naoe Kotomura, Yik Khuan Ho, Huijun Zhi, Sandra Bixler, Michael J. Schell, Chou Zen Giam

Research output: Contribution to journalArticle

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL), a malignancy of CD4+ T cells whose etiology is thought to be associated with the viral trans-activator Tax. We have shown recently that Tax can drastically upregulate the expression of p27 Kip1 and p21CIP1/WAF1 through protein stabilization and mRNA trans-activation and stabilization, respectively. The Tax-induced surge in p21CIP1/WAF1 and p27Kip1 begins in S phase and results in cellular senescence. Importantly, HeLa and SupT1 T cells infected by HTLV-1 also arrest in senescence, thus challenging the notion that HTLV-1 infection causes cell proliferation. Here we use time-lapse microscopy to investigate the effect of Tax on cell cycle progression in two reporter cell lines, HeLa/18x21-EGFP and HeLa-FUCCI, that express enhanced green fluorescent protein (EGFP) under the control of 18 copies of the Tax-responsive 21-bp repeat element and fluorescent ubiquitin cell cycle indicators, respectively. Tax-expressing HeLa cells exhibit elongated or stalled cell cycle phases. Many of them bypass mitosis and become single senescent cells as evidenced by the expression of senescence-associated β-galactosidase. Such cells have twice the normal equivalent of cellular contents and hence are enlarged, with exaggerated nuclei. Interestingly, nocodazole treatment revealed a small variant population of HeLa/18x21-EGFP cells that could progress into mitosis normally with high levels of Tax expression, suggesting that genetic or epigenetic changes that prevent Tax-induced senescence can occur spontaneously at a detectable frequency.

Original languageEnglish (US)
Pages (from-to)3001-3009
Number of pages9
JournalJournal of virology
Volume85
Issue number6
DOIs
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Yang, L., Kotomura, N., Ho, Y. K., Zhi, H., Bixler, S., Schell, M. J., & Giam, C. Z. (2011). Complex cell cycle abnormalities caused by human T-Lymphotropic virus type 1 tax. Journal of virology, 85(6), 3001-3009. https://doi.org/10.1128/JVI.00086-10