title: Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL).
abstract: Adult T cell leukemia/lymphoma (ATLL) has been characterized as one of the most aggressive human neoplasias and its incidence is thought to be caused by both genetic and epigenetic alterations to the host cellular genes of T cells infected with human T cell leukemia virus type I (HTLV-I). A multilobulated nuclear appearance is an important diagnostic marker of ATLL, and we have now identified that the molecular mechanisms underlying these formations occur through microtubule rearrangement via phosphatidylinositol 3-kinase (PI3-kinase) activation by AILIM/ICOS signaling. We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells. This down-regulation of PTEN was found to be essential for the formation of ATLL-type nuclear lobules. Furthermore, PI3-kinase and PTEN activities were observed to be closely associated with cellular proliferation. Thus, our results suggest that alteration of PI3-kinase signaling cascades, as a result of the down-regulation of inositol phosphatases, induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T cell leukemias/lymphomas.
authors.affiliation: Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors.forename: Ryu-ichi
authors.initials: R
authors.lastname: Fukuda
authors.forename: Ayako
authors.initials: A
authors.lastname: Hayashi
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nukada
authors.forename: Rie
authors.initials: R
authors.lastname: Fukui
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Itoh
authors.forename: Katsunari
authors.initials: K
authors.lastname: Tezuka
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ohashi
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
authors.forename: Manabu
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hamanoue
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuji
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D049109:Cell Proliferation; D004789:Enzyme Activation; D015368:Human T-lymphotropic virus 1; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D000072181:Inositol Polyphosphate 5-Phosphatases; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000473:pathology; D008870:Microtubules / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000821:virology
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases