title: Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax.
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 p21(CIP1/WAF1) through protein stabilization and mRNA trans-activation and stabilization, respectively. The Tax-induced surge in p21(CIP1/WAF1) and p27(Kip1) 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.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Yang
authors.forename: Naoe
authors.initials: N
authors.lastname: Kotomura
authors.forename: Yik-Khuan
authors.initials: YK
authors.lastname: Ho
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhi
authors.forename: Sandra
authors.initials: S
authors.lastname: Bixler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.forename: Chou-Zen
authors.initials: CZ
authors.lastname: Giam
mesh_terms: D019677:Artificial Gene Fusion; D002453:Cell Cycle / Q000502:physiology*; D016356:Gene Products, tax / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D018715:Microscopy, Video
chemical_list: D016356:Gene Products, tax; C485184:enhanced green fluorescent protein; C514970:tax protein, Human T-lymphotrophic virus 1; D049452:Green Fluorescent Proteins