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1995 Fiscal Year Final Research Report Summary

REGULATION OF CELL PROLIFERATION BY LYSOPHOSPHATIDIC ACID

Research Project

Project/Area Number 06680679
Research Category

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

Allocation TypeSingle-year Grants
Research Field Cell biology
Research InstitutionOCHANOMIZU UNIVERSITY

Principal Investigator

MURAKAMI Kimiko  OCHANOMIZU UNIVERSITY,DEPARTMENT OF BIOLOGY,ASSISTANT PROFESSOR, 理学部, 講師 (00103557)

Project Period (FY) 1994 – 1995
KeywordsLysophosphatidic acid (LPA) / Cell proliferation / DNA polymerase inhibitor / Xenopus oocytes / LPA receptor / Physarum polycephalum
Research Abstract

The unique lysophosphatidic acid PHYLPA was recently isolated from myxoamoebae of a true slime mold, Physarum polycephalum, as a specific inhibitor of DNA polymerase alpha. This lipid, composed of cyclic phosphate and cyclopropane-containing fatty acid, is the only phospholipid that inhibits DNA polymerase so far investigated. Inhibition of the enzyme is largely the result of competition between the lipid and the template DNA,but not due to a decrease in the affinity of dNTPs to the enzyme. PHYLPA inhibits proliferation of human fibroblast cells in a reversible manner. It elicits an increase in 3', 5'-cyclic adenosine monophosphate in fibroblast cells, and it also elicits inositol phosphate generation, as well as a transient rise in cytoplasmic free Ca^<2+> ion. Compared with the current knowledge about common lysophosphatidic acid (LPA), PHYLPA shows opposite effects in its mode of action on both cell proliferation of fibroblasts and DNA synthesis.
PHYLPA showed selective inhibition of … More a family of DNA polymerase alpha, including DNA polymerase alpha, delta, and epsilon ; but no inhibition of DNA polymerase beta or gamma was observed. To reveal the molecular mechanism of inhibition of DNA polymerases by PHYLPA,four stereo-isomers and some other derivatives were synthesized and their effects on DNA polymerases were studied. Among 8 derivatives, PHYLPA-1 (the natural PHYLPA ; sodium 1-0- [(9'S,10'R) -9', 10' -methanohexadecanoyl]-sn-glycerol 2,3-cyclic phosphate) and PHYLPA-2 (sodium 3-0-[(9'S,10'R) -9', 10' -methanohexadecanoyl] -sn-glycerol 1,2-cyclic phosphate) were strong and specific inhibitors of a family of DNA polymerase alpha. But their stereo-isomers were weak inhibitors, showing an importance of stereochemistry of a cyclopropane-containing fatty acid for the inhibition. Some derivatives having no cyclopropane-containing fatty acids, palmitoyl-, oleoyl-, and palmitoleoyl PHYLPA,showed inhibition to some extent ; but 1-palmitoyl and 1-oleoyl LPA,which has no cyclic-phosphate, did not show an inhibitor activity on DNA polymerases. Hence, the inhibitory activity depends on the structure of cyclic phosphate.
In Xenopus laevis oocytes, both LPA and PHYLPA activate oscillatory Cl^- currents. PHYLPA elicited oscillatory currents only when applied extracellularly and, similar to LPA,evoked homologous desensitization. PHYLPA applied to oocytes previously desensitized by LPA failed to elicit a current, indicating that LPA completely desensitized the PHYLPA receptors. In contrast, when oocytes were desensitized by PHYLPA,LPA still evoked large currents. The lack of heterologous desensitization between PHYLPA and LPA indicates that the former acts on a distinct receptor subpopulation (s), which is also activated by LPA. Less

  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Fukasawa,M.,et al.: "Chinese hamster ovary cells expressing a novel type of acetylated low density lipoprotein receptor. Isolation and characterization." J.Biol.Chem.270. 1921-1927 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Murakami-Murofushi,K.,et al.: "Selective inhibition of DNA polymerase-x family with chemically synthesized derivatives of PHYLPA,a unique Physarum lysophosphatidic acid." Biochim.Biophys.Acta. 1258. 57-60 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sato,y.,et al.: "Side chain structure is critical for the transport of sterols from lysosomes to cytoplascn." Biochim.Biophys.Acta. 1257. 38-46 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kubota,Y.,et al.: "Reduced fidelity of DNA synthesis in cell extracts from chemically induced primary thymic lymphomas of wice." Cancer.Res,. 55. 3777-3780 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Lyliom,K.,et al.: "Xenopus oocytes express multiple receptors for LPA-like lipid mediators." Am.J.Physiol.(印刷中). (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fukasawa, M., et al.: "Chinese hamster ovary cells expressing a novel type of acetylated low density lipoprotein receptor. Isolation and characterization." J.Biol.Chem.270. 1921-1927 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Murakami-Murofushi.K., et al.: "Selective inhibition of DNA polymerase-alpha family with chemically synthesized derivatives of PHYLPA,a unique Physarum lysophosphatidic acid." Biochim.Biophys.Acta. 1258. 57-60 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sato, Y., et al.: "Side chain structure is critical for the transport of sterols from lysosomes to cytoplasm." Biochim.Biophys.Acta. 1257. 38-46 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kubota, Y., et al.: "Reduced fidelity of DNA synthesis in cell extracts from chemically induced primary thymic lymphomas of mice." Cancer Res.55. 3777-3780 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Lyliom, K., et al.: "Xenopus oocytes express multiple receptors for LPA-like lipid mediators." Am.J.Physiol.(in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1997-03-04  

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