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REGULATORY MECHANISM OF RANKL GENE EXPRESSION

Research Project

Project/Area Number 14570188
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionKOBE UNIVERSITY

Principal Investigator

KITAZAWA Riko  KOBE UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, DEPARTMENT OF BIOMEDICAL INFORMATICS, DIVISION OF MOLECULAR PATHOLOGY, ASSISTANT PROFESSOR, 大学院・医学系研究科, 講師 (00273780)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsosteoclast / RANKL / gene promoter / Vitamin D / cAMP responsive element / CpG methylation / cAMP応答配列
Research Abstract

Osteoclast differentiation factor (RANKL) is requisite for the formation and maintenance of osteoclasts from hematopoietic precursors. To clarify the mechanism of RANKL gene expression and osteoclastogenesis, mouse and human RANKL gene promoters were characterized. Both human and mouse RANKL gene promoter shares the common structure, inverted-TATA and CAAT boxes, Runx2/Cbfa-1 binding sites and vitamin D responsive element (VDRE). To elucidate the molecular mechanism of osteolytic bone metastasis, we assessed RANKL gene expression and osteoclastogenesis in osteolytic lesions of mouse experimental model and human bone specimen taken at the autopsy. In both mouse and human osteolytic lesion due to cancer metastasis, RANKL expression was observed on the stromal/osteoblastic cells close to the cancer cell nests. In the mouse model, PTHrP-producing tumor generated osteolytic lesion, whereas non-producing tumor rarely caused RANKL expression and induction of osteoclasts. We further analyzed the effects of PTHrP on RANKL gene transcription. By transient transfection studies using deletion constructs of mouse and human RANKL gene promoter, PTHrP upregulated the transcriptional activity through c-AMP responsive element (CRE) located close to VDRE in both mouse and human. EMSA showed specific protein DNA binding, and the supershift with anti-CREB1 and -ATF2 antibodies. Thus PTHrP induces osteoclastic bone resorption through the RANKL expression on stromal/osteoblastic cells, affording a bone microenvironment conducive to the survival of PTHrP-producing cancer cells.
We have presented our data at various international as well as domestic meeting, and published scientific papers for academic journals.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Kitazawa R: "Vitamin D3 augments osteoclastogenesis via Vitamin D-responsive element of mouse RANKL gene promoter"BBRC. 290. 650-655 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S: "Epigenetic control of mouse receptor activator of NFkB ligand gene expression"BBRC. 293. 126-131 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S: "RANK ligand is a prerequisite for cancer-associated osteolytic lesions"J Pathol. 198. 228-236 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S: "Vitamin D3 Supports Osteoclastogenesis via Functional Vitamin D Response Element of Human RANKL Gene Promoter"J Cell Biochem. 89. 771-777 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Srivastava S: "Receptor Activator of NF-kB Ligand (RANKL) Induction via Jak2 and Stat 5a in Mammary Epithelial Cells"J Biol Chem. 278. 46171-46178 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa R, Kitazawa S.: "Vitamin D3 augments osteoclastogenesis via vitamin D-responsive element of mouse RANKL gene promoter."Biochem Biophys Res Com. 290. 650-655 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S, Kitazawa R.: "RANK ligand is requisite for cancer-associated osteolytic lesions."J Pathol. 198. 228-236 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S, Kitazawa R.: "Epigenetic control of mouse receptor activator of NFkappaB ligand."Biochem Biophys Res Com. 293. 126-131 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ishida A, Fujita N, Kitazawa R, Tsuruo T: "Transforming growth factor-beta induces expression of receptor activator of NFkappaB ligand in vascular endothelial cells derived from bone."J Biol Chem. 277. 26217-26224 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mori H, Kitazawa R, Mizuki S, Nose M, Maeda S, Kitazawa S: "RANK ligand, RANK and OPG expression in type II collagen-induced arthritis mouse."Histochem Cell Biol. 117. 283-292 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa R, Kobayashi A, Maeda S, Kitazawa S: "Expression of parathyroid hormone-related protein (PTHrP) in parathyroid tissues of normal and pathological conditions."Histol Histopathol. 17. 179-184 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa R, Kitazawa S, Kajimoto K, Sowa H, Sugimoto T, Chihara K, Maeda S: "Parathyroid hormone-related protein (PTHrP) expression in multiple myeloma : a case report."Pathol Int. 52. 63-68 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S, Kondo T, Kitazawa R.: "Detection of mRNA at early phase by in situ hybridization at electron microscopic level."Denshikenbikyou. 37. 89-91 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kajimoto K, Kitazawa R, Kitazawa S.: "Characterization of the 5'-flanking region of the human RANK ligand gene."Kobe Daigaku Igakubu Kiyo. 62. 143-150 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo T, Kitazawa R, Maeda S, Kitazawa S.: "Myxoid leiomyosarcoma of the uterus."Shindan Byori. 19. 247-248 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kim E, Kitazawa R, Kondo T, Kitazawa S.: "An autopsy case of combined hepatocellular and cholangiolocellular carcinoma."Shindan Byori. 19. 343-345 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S, Kajimoto K, Kondo T, Kitazawa R.: "Vitamin D3 supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter."J Cell Biochem. 89. 771-777 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Srivastava S, Matsuda M, Hou Z, Bailey JP, Kitazawa R, Herbst MP, Horseman ND.: "Receptor activator of NF-kB ligand (RANKL) induction via Jak2 and Stat5a in mammary epithelial cells."J Biol Chem. 278. 46171-46178 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yano S, Sugimoto T, Tsukamoto T, Chihara K, Kobayashi A, Kitazawa S, Maeda S, Kitazawa R.: "Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas."Eur J Endocrinol. 148. 403-411 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saijo M, Kitazawa R, Nakajima M, Kurosaka M, Maeda A, Kitazawa S: "Heparanase mRNA expression during fracture repair in mouse."Histochem Cell Biol. 120. 493-503 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Darwanto A, Kitazawa R, Maeda A, Kitazawa S.: "MeCP2 and promoter methylation cooperatively regulate E-cadherin gene expression in colorectal carcinoma."Cancer Sci. 94. 442-447 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Makino T, Sugimoto T, Kaji H, Yamaguchi T, Kitazawa R, Yamauchi M, Sowa H, Chen Q, Nomura R, Tsukamoto T, Chihara K.: "Functional giant parathyroid cyst with high concentration of CA 19-9 in cystic fluid."Endocr J. 50. 215-219 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujimoto M, Kitazawa R, Kondo T, Maeda S, Kitazawa S.: "Three cases of malignant pancreatic tumor with intraglomerular metastasis."Sindan Byori. 20. 144-145 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo T, Kitazawa R, Hirata K, Kitazawa S.: "A case of cardiac tamponade due to rupture of mycotic aortic aneurysm."Sindan Byori. 20. 236-238 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kondo T, Kitazawa R, Wada H, Kitazawa S.: "An autopsy case of Becker muscular dystrophy."Sindan Byori. 20. 283-285 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kobayashi N, Kitazawa S, Kitazawa R, Kondo T, Fujimoto M, Kishimoto K, Ishida T, Inoue N, Yokoyama M, Maeda S.: "A case of old myocardial infarction with interstitial pneumonia and drug induced hepatitis and pancreatitis during amiodarone therapy."Sindan Byori. 23. 175-159 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hirano M, Yamasaki K, Sakurai T, Kondoh T, Ryu Y, Okada H, Kitazawa S, Kitazawa R, Maeda S, Katafuchi T, Tamura S.: "Measurement of blood vessels diameter for angiography using refraction contrast imaging."Jpn J Med Phys. 52. 63-68 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa R, Kitazawa S.: "Gene expression in osteolytic bone metastasis of malignant tumor."Byori-to-Rinsho. 22. 285-289 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kitazawa S: "Vitamin D3 Supports Osteoclastogenesis via Functional Vitamin D Response Element of Human RANKL Gene Promoter"J Cell Biochem. 89・4. 771-777 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Srivastava S: "Receptor Activator of NF-kB Ligand (RANKL) Induction via Jak2 and Stat5a in Mammary Epithelial Cells"J Biol Chem. 278・46. 46171-46178 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saijo M: "Heparanase mRNA Expression During Fracture Repair in Mouse"Histochem Cell Biol. 120・6. 493-503 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yano S: "Decrease in Vitamin D Receptor and Calcium-Sensing Receptor in Highly Proliferative Parathyroid Adenomas"Eur J Endocrinol. 148・4. 403-411 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Darwanto A: "MeCP2 and Promoter Methylation Cooperatively Regulate E-Cadherin Gene Expression in Colorectal Carcinoma"Cancer Sci. 94・5. 442-447 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Makino T: "Functional Giant Parathyroid Cyst with High Concentration of CA19-9 in Cystic Fluid"Endocr J. 50・2. 215-219 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kitazawa S, Kitazawa R.: "RANK ligand is a prerequisite for cancer-associated osteolytic lesions"J Pathol. 198・2. 228-236 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kitazawa S, Kitazawa R.: "Epigenetic control of mouse receptor activator of NFkB ligand gene expression"BBRC. 293・1. 126-131 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mori H, Kitazawa R, Mizuki S et al.: "RANK ligand, RANK and OPG expression in type II collagen-induced arthritis mouse"Histochem Cell Biol. 117・3. 283-292 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kitazawa R, Kitazawa S.: "Vitamin D3 augments osteoclastogenesis via Vitamin D-responsive element of mouse RANKL gene promoter"BBRC. 290・2. 650-655 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kitazawa R, Kobayashi A, Maeda S, Kitazawa S: "Expression of parathyroid hormone-related protein (PTHrP) in parathyroid tissues of normal and pathological conditions"Histol Histopathol. 17・1. 170-184 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kitazawa R, Kitazawa S, Kajimoto K et al.: "Parathyroid hormone-related protein (PTHrP) expression in multiple myeloma : a case report"Pathol Int. 52・1. 63-68 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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