title: Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV-1-infected T cells through enhanced NF-kappaB activity.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia (ATL). Aurora A, a mitotic checkpoint protein, is overexpressed in human cancer cells. The cell cycle-dependent turnover of Aurora A is regulated by E3 ubiquitin ligases such as checkpoint with fork head-associated and ring finger (CHFR). Here, we found overexpression of Aurora A protein in HTLV-1-infected T-cell lines and primary ATL cells. The expression of CHFR mRNA was reduced in these cells by abnormal methylation of CHFR promoter region. Knockdown of Aurora A using small interfering RNA suppressed the growth of HTLV-1-infected T-cell line. Transfection of Aurora A expression plasmid enhanced Tax-induced nuclear factor-kappaB (NF-kappaB) reporter activity. Transfection of CHFR expression plasmid into an HTLV-1-infected T-cell line reduced cell growth, Aurora A protein level and constitutive NF-kappaB reporter activity. Aurora kinase inhibitor suppressed the growth and survival of HTLV-1-infected T-cell lines and primary ATL cells. It also reduced constitutive NF-kappaB activity in an HTLV-1-infected T-cell line by reducing IkappaB kinase beta phosphorylation and the expression of antiapoptotic protein survivin. Our results suggested that loss of CHFR expression resulted to accumulation of Aurora A, which increased NF-kappaB activity. These findings highlight the critical role of Aurora A in HTLV-1-infected T cells, making this molecule a potentially suitable target for future therapies for ATL.
authors.affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomita
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nakazato
authors.forename: Taeko
authors.initials: T
authors.lastname: Okudaira
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsuda
authors.forename: Jun-Nosuke
authors.initials: JN
authors.lastname: Uchihara
authors.forename: Naoya
authors.initials: N
authors.lastname: Taira
authors.forename: Kazuiku
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Masachika
authors.initials: M
authors.lastname: Senba
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D017209:Apoptosis; D064127:Aurora Kinases; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D019175:DNA Methylation; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology / Q000821:virology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D018797:Cell Cycle Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases