Int J Biochem Mol Biol 2012;3(1):95-104
Original Article
HTLV-I Tax regulates the cellular proliferation through the down-regulation of PIP3-
phosphatase expressions via the NF-κB pathway
Ryu-ich Fukuda, Kiyohito Tsuchiya, Koji Suzuki, Katsuhiko Itoh, Jun Fujita, Atae Utsunomiya, Takashi Tsuji
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, 278-
8510, Japan; Research Institute of Science and Technology, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Department of
Clinical Molecular Biology, Faculty of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan; Department of Hematology, Imamura Bun-in
Hospital, Kagoshima, Kagoshima 890-0064, Japan
Received March 8, 2012; accepted March 15, 2012; Epub March 20, 2012; Published March 30, 2012
Abstract: An oncogenic retrovirus, human T-cell leukemia virus type I (HTLV-I), encodes an oncoprotein, Tax, which plays critical roles in
leukemogenesis of adult T-cell leukemia/lymphoma (ATLL) through the pleiotropic actions such as transcriptional regulation, cell cycle control,
and transformation. We have previously reported that PTEN and SHIP-1, PIP3 inositol phosphatases that negatively regulate the PI3-kinase
signaling cascade, are disrupted in ATLL neoplasias. Overactivation of PI3-kinase signaling has an essential role in onset of ATLL. We report
here that both PTEN and SHIP-1 are downregulated by Tax through the NF-κB signaling pathway. Tax expression upregulated phosphorylated
Akt, a downstream serine/threonine kinase in the PI3-kinase signaling cascade. Activation of NF-κB pathway also suppressed these
phosphatases. An IκBΔN mutant which inhibits the activation of NF-κB prevented PIP3 phosphatase downregulation by Tax. The underlying
mechanism of NF-κB mediated suppression of PIP3 phosphatases involved sequestration of the coactivator p300 by p65. These down-
regulations of PIP3 phosphatases were found to be essential for the Tax-induced cell proliferation. Thus, our results suggest that HTLV-I Tax
downregulates PIP3 phosphatases through the NF-κB pathway, resulting in increased activation of the PI3-kinase signaling cascade in human
T-cells and contributing to leukemogenesis. (IJBMB1203002).
Keywords: HTLV-I, Tax, PTEN, SHIP-1, NF-κB
Address all correspondence to:
Dr. Takashi Tsuji
Research Institute of Science and Technology
Tokyo University of Science
Noda, Chiba, 278-8510, Japan.
Tel: +81-4-7122-9711; Fax: +81-4-7125-1841
E-mail: t-tsuji@rs.noda.tus.ac.jp Or: t-tsuji@nifity.com
Original Article
HTLV-I Tax regulates the cellular proliferation through the down-regulation of PIP3-
phosphatase expressions via the NF-κB pathway
Ryu-ich Fukuda, Kiyohito Tsuchiya, Koji Suzuki, Katsuhiko Itoh, Jun Fujita, Atae Utsunomiya, Takashi Tsuji
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, 278-
8510, Japan; Research Institute of Science and Technology, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Department of
Clinical Molecular Biology, Faculty of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan; Department of Hematology, Imamura Bun-in
Hospital, Kagoshima, Kagoshima 890-0064, Japan
Received March 8, 2012; accepted March 15, 2012; Epub March 20, 2012; Published March 30, 2012
Abstract: An oncogenic retrovirus, human T-cell leukemia virus type I (HTLV-I), encodes an oncoprotein, Tax, which plays critical roles in
leukemogenesis of adult T-cell leukemia/lymphoma (ATLL) through the pleiotropic actions such as transcriptional regulation, cell cycle control,
and transformation. We have previously reported that PTEN and SHIP-1, PIP3 inositol phosphatases that negatively regulate the PI3-kinase
signaling cascade, are disrupted in ATLL neoplasias. Overactivation of PI3-kinase signaling has an essential role in onset of ATLL. We report
here that both PTEN and SHIP-1 are downregulated by Tax through the NF-κB signaling pathway. Tax expression upregulated phosphorylated
Akt, a downstream serine/threonine kinase in the PI3-kinase signaling cascade. Activation of NF-κB pathway also suppressed these
phosphatases. An IκBΔN mutant which inhibits the activation of NF-κB prevented PIP3 phosphatase downregulation by Tax. The underlying
mechanism of NF-κB mediated suppression of PIP3 phosphatases involved sequestration of the coactivator p300 by p65. These down-
regulations of PIP3 phosphatases were found to be essential for the Tax-induced cell proliferation. Thus, our results suggest that HTLV-I Tax
downregulates PIP3 phosphatases through the NF-κB pathway, resulting in increased activation of the PI3-kinase signaling cascade in human
T-cells and contributing to leukemogenesis. (IJBMB1203002).
Keywords: HTLV-I, Tax, PTEN, SHIP-1, NF-κB
Address all correspondence to:
Dr. Takashi Tsuji
Research Institute of Science and Technology
Tokyo University of Science
Noda, Chiba, 278-8510, Japan.
Tel: +81-4-7122-9711; Fax: +81-4-7125-1841
E-mail: t-tsuji@rs.noda.tus.ac.jp Or: t-tsuji@nifity.com
 |  |  |  |  |  |  |