Hedgehog signaling in murine and human

• Project/Area Number: 24591502
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Chiba University
• Principal Investigator: FUJII Katsunori 千葉大学, 医学(系)研究科(研究院), 講師 (70344992)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ヘッジホッグ / 形態形成 / 癌形成 / 高発癌性遺伝 / Gorlin症候群 / ゴーリン症候群 / PTCH1 / シグナル伝達 / SMO / GLI

Outline of Final Research Achievements

Hedgehog signaling is a pivotal developmental pathway that comprises hedgehog, PTCH1, SMO, and GLI proteins. Mutations in PTCH1 are responsible for Gorlin syndrome, which is characterized by developmental defects and tumorigenicity. In order to elucidate the mechanism by which transduction of the hedgehog signal is regulated in tissues, we employed murine C3H10T1/2 cells and human fibroblasts. We investigated GLI1 transcription to assess native signal transduction, and then treated cells with a recombinant human hedgehog protein with or without serum deprivation. Hedgehog stimulation and nutritional deprivation synergistically enhanced GLI1 transcription levels, which was blocked more efficiently by vismodegib. These results indicated that the hedgehog stimulation and nutritional deprivation synergistically activated the hedgehog signaling pathway. These fibroblasts may become a significant tool for predicting the efficacies of hedgehog molecular-targeted therapies such as vismodegib.

Research Products

• [Journal Article] Hedgehog signaling is synergistically enhanced by nutritional deprivation and ligand stimulation in human fibroblasts of Gorlin syndrome (2015)
  • Author(s): Mizuochi H, Fujii K, Shiohama T, Uchikawa H, Shimojo N
  • Journal Title: Biochem Biophys Res Commun Volume: 457 Issue: 3 Pages: 318-323
  • DOI: 10.1016/j.bbrc.2014.12.108
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Oxidative stress-induced JNK1 phosphorylation inhibits hedgehog signalling and osteoblast differentiation (2014)
  • Author(s): Shiohama T, Fujii K, Uchikawa H, Takatani T, Mizuochi H, Kohno Y
  • Journal Title: Cell Biology International Reports Volume: 9999 Pages: 1-10
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gorlin syndrome (nevoid basal cell carcinoma syndrome): update and literature review (2014)
  • Author(s): Fujii K, Miyashita T
  • Journal Title: Pediatric International Volume: 56 Issue: 5 Pages: 667-674
  • DOI: 10.1111/ped.12461
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ゴーリン症候群 (2014)
  • Author(s): 藤井克則、宮下俊之
  • Journal Title: 日本臨牀 新領域別症候群シリーズNo. 28 神経症候群 Volume: 28 Pages: 581-4
• [Journal Article] Gorlin症候群 (2014)
  • Author(s): 藤井克則、宮下俊之
  • Journal Title: 日本臨床 新領域別症候群シリーズNo. 29 神経症候群 Volume: 29 Pages: 744-7
• [Journal Article] Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. (2013)
  • Author(s): Fujii. K., Ohashi, H. ,Suzuki, M., Hatsuse, H., Shiohama, T., Uchikawa, H., and Miyashita, T.
  • Journal Title: Fam. Cancer Volume: 12 Issue: 4 Pages: 611-614
  • DOI: 10.1007/s10689-013-9623-1
  • Peer Reviewed
• [Journal Article] 14-3-3 proteins, particularly of the epsilon isoform, are detectable in cerebrospinal fluids of cerebellar diseases in children. (2013)
  • Author(s): Fujii K, Uchikawa H, Tanabe Y, Omata T, Nonaka I, Kohno Y.
  • Journal Title: Brain and Development Volume: 35 Issue: 6 Pages: 555-560
  • DOI: 10.1016/j.braindev.2012.09.007
  • Peer Reviewed
• [Journal Article] Artery tortuosity syndrome exhibiting early-onset emphysema with novel compound heterozygous SLC2A10 mutations. (2013)
  • Author(s): Takahashi Y, Fujii K, Yoshida A, Morisaki H, Kohno Y, Morisaki T.
  • Journal Title: American Journal of Medical Genetics Volume: 161A Issue: 4 Pages: 856-859
  • DOI: 10.1002/ajmg.a.35776
  • Peer Reviewed
• [Journal Article] Reversible white matter lesions during ketogenic diet therapy in glucose transporter 1 deficiency syndrome. (2013)
  • Author(s): Shiohama T, Fujii K, Takahashi S, Nakamura F, Kohno Y.
  • Journal Title: Brain and Development Volume: 49 Issue: 6 Pages: 493-496
  • DOI: 10.1016/j.pediatrneurol.2013.06.004
  • Peer Reviewed
• [Journal Article] Sudden onset odontoid fracture caused by cervical instability in hypotonic cerebral palsy. (2013)
  • Author(s): Shiohama T, Fujii K, Kitazawa K, Takahashi A, Maemoto T, Honda A.
  • Journal Title: Brain and Development Volume: 35 Issue: 10 Pages: 925-928
  • DOI: 10.1016/j.braindev.2012.11.012
  • Peer Reviewed
• [Journal Article] Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. (2013)
  • Author(s): Fujii K, Ohashi H, Suzuki M, Hatsuse H, Shiohama T, Uchikawa H, Miyashita T.
  • Journal Title: Familial Cancer Volume: 1 Pages: 1-1
  • Peer Reviewed
• [Journal Article] 14-3-3 Proteins, particularly of the epsilon isoform, are detectable in cerebrospinal fluids of cerebellar diseases in children. (2013)
  • Author(s): Fujii K, Uchikawa H, Tanabe Y, Omata T, Nonaka I, Kohno Y.
  • Journal Title: Brain and Development Volume: 1 Pages: 1-1
  • Peer Reviewed
• [Journal Article] Heterozygous tandem duplication within the PTCH1 gene results in nevoid basal cell carcinoma syndrome. (2012)
  • Author(s): Kosaki R, Nagao K, Kameyama K, Suzuki M, Fujii K, Miyashita T.
  • Journal Title: American Journal of Medical Genetics A Volume: 158A Pages: 1724-8
• [Journal Article] Selective haploinsufficiency of longer isoforms of PTCH1 protein can cause nevoid basal cell carcinoma syndrome. (2012)
  • Author(s): Suzuki M, Hatsuse H, Nagao K, Takayama Y, Kameyama K, Kabasawa Y, Omura K, Yoshida M, Fujii K, Miyashita T.
  • Journal Title: Jounal of human genetics Volume: 57 Pages: 422-6
• [Presentation] Hedgehog signaling is synergistically enhanced by nutritional deprivation and ligands stimulation in human fibroblasts of Gorlin syndrome (2014)
  • Author(s): Hiromi Mizuochi, Katsunori Fujii, Tadashi Shiohama, Hideki Uchikawa, Toshiyuki Miyashita, Naoki Shimojo
  • Organizer: 2015 Hedgehog meeting
  • Place of Presentation: Ann Arbour, Michigan, USA
  • Year and Date: 2014-08-04 – 2014-08-08
• [Presentation] Oxidative stress-induced JNK1 phosphorylation inhibits hedgehog signaling and osteoblast differentiation (2014)
  • Author(s): Katsunori Fujii, Tadashi Shiohama, Hiromi Mizuochi, Hideki Uchikawa, Tomozumi Takatani, Toshiyuki Miyashita, Yoichi Kohno
  • Organizer: 2015 Hedgehog meeting
  • Place of Presentation: Ann Arbour, Michigan, USA
  • Year and Date: 2014-08-04 – 2014-08-08
• [Presentation] Hedgehog signaling is enhanced by nutritional deprivation in human fibroblasts of Gorlin syndrome (2014)
  • Author(s): Hiromi Mizuochi, Katsunori Fujii, Tadashi Shiohama, Hideki Uchikawa, Naoki Shimojo
  • Organizer: 日本小児神経学会学術総会
  • Place of Presentation: Tahoe City, California, USA
  • Year and Date: 2014-05-29 – 2014-05-31
• [Remarks] 千葉大学小児科神経グループ
  • URL: http://www.pediatrics-chiba-u.org/research/group_nerve.html
• [Remarks] 千葉大学大学院医学研究院小児病態学
  • URL: http://www.pediatrics-chiba-u.org/research/group_nerve.html