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Intracellular Signal Transduction and Topological Change of Intranuclear DNA in the Differentiation of Human Leukemic HL-60 Cells.

Research Project

Project/Area Number 03671184
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionMie University

Principal Investigator

NISHIKAWA Masakatsu  Mie University Hospital, Lecturer., 医学部附属病院, 講師 (30144257)

Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1992: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1991: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsHuman leukemic HL-60 cell / Protein kinase C / Cell differentiation / Retinoic acid / 12-o-tetradecanoylphorbol 13-acetate(TPA) / Protein phosphatase / Calyculin-A / Topoisomerase II / トポイソメラーゼ / ホスファターゼ / レチノイド / 白血病細胞 / Cキナ-ゼ活性 / Cキナ-ゼアイソザイム / 血球分化 / トポイソメラ-ゼ
Research Abstract

Human myelogenous HL-60 leukemia cells can be induced to differentiate into either monocyte/macrophage-like cells or into granulocytes by various chemical agents. These include 1,25-dihydroxyvitamin D_3(1,25-(OH)_2D_3) and 12-o-tetra-decanoylphorbol 13-acetate(TPA), which mediate monocytic differentiation, and all-trans retinoic acid(ATRA) for granulocytic differentiation. The activation, translocation and subsequent down-regulation of protein kinase C(PKC) appears to be essential for TPA-induced differentiation of HL-60 cells into macrophage-like cells. This is evidenced by pharmacological methods using PKC inhibitors such as H-7 and sphinganine, and investigations with TPA-resistant HL-60 variant(HL-60R) cells. Among PKC isozymes, PKC-beta may be crucial signal in the regulation of TPA-induced HL-60 cell differentiation, and the resistance of HL-60R cells to TPA induction may be due to the selective depression of cytosolic PKC-beta. The levels of both PKC activity and the expression … More of PKC-alpha, -beta, -gamma isoforms have been shown to increase during HL-60 differentiation induced by DMSO and ATRA. 1,25-(OH)_2D_3 induced monocytic differentiation is also associated with an in- crease in both PKC activity and the expression of PKC-alpha and -beta. These results suggest that PKC activation and/or modulation of its isoenzyme expression play key roles in regulating the responses of hematopoietic cells to both growth factors and non-physiological inducers of cell growth and differentiation.
The regulation of protein function by phosphorylation necessarily requires protein phosphatases(PPs) in addition to protein kinases. It is conceivable that PPs may also be involved in the process of HL-60 cell differentiation. Potent inhibitors of PP1 and PP2A, calyculin-A(CAL-A) and okadaic acid could augment ATRA-induced granulocytic differentiation, whereas the differentiation toward macrophage lineage by TPA was unchanged in the presence of CAL-A. Treatment of HL-60 cells with ATRA led to a dramatic decrease in the activity of PP and PP2A protein expression. The mRNA level of PP2A was markedly decreased within 3 hrs after addition of ATRA. Thus, down regulation of PP2A may be involved in differentiation events of HL-60 cells induced by ATRA.
We are now examining the modulation/expression of topoisomerase II induced by differentiation inducers in order to know the regulatory roles of protein phosphorylation in the topological changes of nuclear DNAs during HL-60 cell differentiation. Less

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] KOADA F.ea al.: "Expression of three major protein kinase C isozymes in various types of human leukemic cells." Cancer Res.51. 4271-4278 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] KATAYAMA N.et al.: "A role for protein kinase C in the growth of human erythroid progenitor cells." Leukemia Res.16. 145-151 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] NISHIKAWA M.et al.: "The expression and possible roles of protein kinase C in hematopoietic cells." Leukemia and Lymphoma.8. 201-211 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] MORITA K.et al.: "Augmentation of retinoic acid-induced granulocytic differentiation in HL-60 leukemia cells by serine/theronine protein phoshatase inhibitors." FEBS Lett.314. 340-344 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] TAWARA I.et al.: "Down regulation by retinoic acid of catalytic subunit of protein phosphatase type 2A during granulocytic differentiation of HL-60 cells." FEBS Lett.(1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Komada F, Nishikawa M, Uemura Y, Morita K, Hidaka H, and Shirakawa S.: "Expression of three major protein kinase C isozymes in various types of human leukemic cells." Cancer Res.51. 4271-4278 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Katayama N, Nishikawa M, Shimizu N, Komada F, Sekine T, Minami N and Shirakawa S.: "A role for protein kinase C in the growth of human erythroid progenitor cells." Leukemia Res.16. 145-151 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishikawa M and Shirakawa S.;: "The expression and possible roles of protein kinase C in hematopoietic cells." Leukemia & Lymphoma. 8. 201-211 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Morita K, Nishikawa M, Kobayashi K, Deguchi K, Ito M, Nakano T, Shima H, Nagao M, Kuno T, Tanaka C and Shirakawa S: "Augmentation of retinoic acid-induced granulocytic differentiation in HL-60 leukemia cells by serine/threonine protein phosphatase inhibitors." FEBS Lett.314. 340-344 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Tawara I, Nishikawa M, Morita K, Kobayashi K, Toyoda H, Omay S.B., Shima H, Nagao M, Kuno T, Tanaka C and Shirakawa S: "Down regulation by retinoic acid of catalytic subuni of protein phosphatase type 2A during granulocytic differentiation of HL-60 cells." FEBS Lett.(1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Katayama N et al.: "A role for protein kinase C in the growth of human erythroid progenitor cells." Leukemia Res.16. 145-151 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nishikawa M et al.: "The expression and possible roles of protein kinase C in hematopoietic cells." Leukemia and Lymphoma. 8. 201-211 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Morita K et al.: "Augmentation of retinoic acid-induced granulocytic differentiation in HL-60 leukemic cells by serine/threonine protein phosphatase inhibitors." FEBS Lett.314. 340-344 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Komada F.et al.: "Expression of three major protein kinase C isozymes in various types of human leukemic cells." Cancer Research. 51. 4271-4278 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nishikawa M.et al.: "the roles and ewpressions of protein kinase C in hematopoietic cell." Leukemia and Lymphoma.(1992)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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