Enhancement of drug-sensitivity through the reactivation of mutant p53

• Project/Area Number: 23501278
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: OZAKI TOSHINORI 千葉県がんセンター(研究所), その他部局等, 研究員 (40260252)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: がん抑制遺伝子

Research Abstract

We have identified co-chaperon human DnaJC7 as one of the binding partners of mutant p53. According to our immunoprecipitation experiments, DnaJC7 was associated with mutant p53 as well as wild-type p53 in mammalian cultured cells. Of note, DnaJC7 promoted the dissociation of MDM2 from wild-type p53, and thereby extended its half-life and stimulated its transcriptional as well as pro-apoptotic activity. In addition, luciferase reporter assays demonstrated that DnaJC7 has an ability to reduce the inhibitory effect of mutant p53 on wild-type p53. Taken together, our present results strongly suggest that DnaJC7 might enhance the drug-sensitivity of malignant cancerous cells through the physical and functional interactions with wild-type p53 and/or mutant p53.

Research Products

• [Journal Article] Inhibition of malignant phenotypes of human osteosarcoma cells by a gene silencer Pyrrole-Imidazole polyamide targeting E-box (2014)
  • Author(s): Taniguchi M, Fujiwara K, Nakai Y, Ozaki T, Koshikawa N, Kojima T, Kataba M, Oguni A, Matsuda H, Yoshida Y, Tokuhashi Y, Fukuda N, Ueno T, Soma M, and Nagase H
  • Journal Title: FEBS Open Bio Volume: 4 Pages: 328-334
  • Peer Reviewed
• [Journal Article] Receptor-type protein tyrosine phosphatase к (PTPRK) directly dephosphorylates CD133 and regulates downstream AKT activation (2014)
  • Author(s): Shimozato O, Waraya M, Nakashima K, Soda H, Takiguchi N, Yamamoto H, Takenobu H, Uehara H, Ikeda E, Matsushita S, Kubo N, Nakagawara A, Ozaki T, Kamijo T
  • Journal Title: Oncogene Volume: (in press)
  • Peer Reviewed
• [Journal Article] Inhibition of malignant phenotypes of human osteosarcoma cells by a gene silencer, a pyrrole-imidazole polyamide, which targets E-box. (2014)
  • Author(s): 134. Taniguchi M, Nakai Y, Ozaki T, Koshikawa N, Kojima T, Kataba M, Oguni A, Matsuda H, Yoshida Y, Tokuhashi Y, Fukuda N, Ueno T, Soma T, Nagase H.
  • Journal Title: FEBS Open Bio Volume: 4 Issue: 1 Pages: 328-334
  • DOI: 10.1016/j.fob.2014.03.004
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-type protein tyrosine phosphatase κ (PTPRK) directly dephosphorylates CD133 and regulates downstream AKT activation. (2014)
  • Author(s): Shimozato O, Waraya M, Nakashima K, Soda H, Takiguchi N, Yamamoto H, Takenobu H, Uehara H, Ikeda E, Matsushita S, Kubo N, Nakagawara A, Ozaki T, Kamijo T.
  • Journal Title: Oncogene Volume: 未定
  • Peer Reviewed
• [Journal Article] Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2 (2013)
  • Author(s): Kubo N, Wu D, Yoshihara Y, Sang M, Nakagawara A, Ozaki T
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 430 Pages: 1034-1039
  • Peer Reviewed
• [Journal Article] Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage (2013)
  • Author(s): Ozaki T,Wu D, Sugimoto H, Nagase H, Nakagawara A
  • Journal Title: Cell Death Dis.
  • Peer Reviewed
• [Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression (2013)
  • Author(s): Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawara A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A
  • Journal Title: J. Clin. Invest. Volume: 123 Pages: 2935-2947
  • Peer Reviewed
• [Journal Article] NFBD1/MDC1 is phosphorylated by PLK1 and controls G2/M transition through the regulation of a TOPOIIα-mediated decatenation checkpoint (2013)
  • Author(s): Ando K, Ozaki T, Hirota T, Nakagawara A
  • Journal Title: PLoS One
  • Peer Reviewed
• [Journal Article] Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2. (2013)
  • Author(s): Kubo N, Wu D, Yoshihara Y, Sang M, Nakagawara A, Ozaki T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 430 Issue: 3 Pages: 1034-1039
  • DOI: 10.1016/j.bbrc.2012.11.121
  • Peer Reviewed
• [Journal Article] Runt-related transcription factor 2 (RUNX2) inhibits p53- dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. (2013)
  • Author(s): Ozaki T, Wu D, Sugimoto H, Nagase H, Nakagawara A.
  • Journal Title: Cell Death Dis. Volume: e610 Issue: 4 Pages: e610-e610
  • DOI: 10.1038/cddis.2013.127
  • Peer Reviewed
• [Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. (2013)
  • Author(s): Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A.
  • Journal Title: J Clin Invest. Volume: 123 Issue: 7 Pages: 2935-47
  • DOI: 10.1172/jci65988
  • Peer Reviewed
• [Journal Article] NFBD1/MDC1 is phosphorylated by PLK1 and controls G2/M transition through the regulation of a TOPOIIα-mediated decatenation checkpoint. (2013)
  • Author(s): Ando K, Ozaki T, Hirota T, Nakagawara A.
  • Journal Title: PLoS One Volume: e82744 Issue: 12 Pages: 0-0
  • DOI: 10.1371/journal.pone.0082744
  • Peer Reviewed
• [Journal Article] Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 in response to DNA damage through complex formation and acetylation. (2013)
  • Author(s): Wu D, Ozaki T, Yoshihara Y, Kubo N, Nakagawara A.
  • Journal Title: J. Biol. Chem. Volume: 288 Pages: 1353-1364
  • Peer Reviewed
• [Journal Article] Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2. (2013)
  • Author(s): Kubo N, Wu D, Yoshihara Y, Sang M, Nakagawara A, Ozaki T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 430 Pages: 1034-1039
  • Peer Reviewed
• [Journal Article] Runt-related transcription factor 2 (RUNX2) inhibits p53- dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. (2013)
  • Author(s): Ozaki T, Wu D, Sugimoto H, Nagase H, Nakagawara A.
  • Journal Title: Cell Death Disease Volume: 未定
  • Peer Reviewed
• [Journal Article] p53 依存性のDNA 損傷応答機構における RUNX2 の新たな役割 (2013)
  • Author(s): 尾崎俊文、永瀬浩喜、中川原章
  • Journal Title: 生化学 Volume: 未定
  • Peer Reviewed
• [Journal Article] Inhibitory role of E2F-1 in the regulation of tumor suppressor p53 during DNA damage response (2012)
  • Author(s): Yoshihara Y, Wu D, Kubo N, Sang M, Nakagawara A, Ozaki T
  • Journal Title: Biochem, Biophys, Res. Commun. Volume: 421 Pages: 57-63
  • Peer Reviewed
• [Journal Article] CREB represses p53-dependent transactivation of MDM2 through the complex formation with p53 and contributes to p53-mediated apoptosis in response to glucose deprivation (2011)
  • Author(s): Okoshi R, Kubo N, Nakashima K, Shimozato O, Nakagawara A, Ozaki T
  • Journal Title: Biochem, Biophys, Res. Commun. Volume: 406 Pages: 79-84
  • Peer Reviewed
• [Journal Article] Role of p53 in cell death and human cancers (2011)
  • Author(s): Ozaki T, Nakagawara A
  • Journal Title: Cancers Volume: 3 Pages: 994-1013
  • Peer Reviewed
• [Journal Article] DNA損傷刺激に応答したp53の活性化機構におけるRUNX3の新たな役割とアポトーシス誘導 (2011)
  • Author(s): 尾崎俊文、山田千寿、中川原章
  • Journal Title: 生化学 Volume: 83 Pages: 751-754
  • NAID: 10029575150
  • Peer Reviewed
• [Presentation] RUNX2 inhibits p53-dependent apoptosis following DNA damage in collaboration with HDAC6 (2013)
  • Author(s): Ozaki T, Sugimoto H, Nakagawara A, Nagase H
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] Phosphorylation of NFBD1/MDC1 by plk1 regulates decatenation checkpoint-mediated G2/M transition (2013)
  • Author(s): Ando K, Ozaki T, Hirota T, Nakagawara A
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-04
• [Presentation] DNA 損傷に応答したアポトーシス誘導過程における複合体形成を介した RUNX1 による p53 の制御機構の解析 (2012)
  • Author(s): 呉丹、久保奈津美、尾崎俊文、中川原章
  • Organizer: 第 71 回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] DNA 損傷応答過程におけるp53 と RUNX2 との機能的相互作用の解析 (2012)
  • Author(s): 尾崎俊文 呉丹、久保奈津美、上條岳彦、中川原章
  • Organizer: 第 71 回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] DNA損傷に応答したRUNX1によるp53の活性化機構の解析 (2011)
  • Author(s): 呉丹、久保奈津美、吉原由佳里、尾崎俊文、中川原章
  • Organizer: 第３４回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] p53依存性アポトーシス誘導過程におけるRUNX2の役割 (2011)
  • Author(s): 久保奈津美、呉丹、中川原章、上條岳彦、尾崎俊文
  • Organizer: 第７０回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] RUNX2 inhibits p53-dependent apoptosis following DNA damage in collaboration with HDAC6
  • Author(s): Ozaki T, Sugimoto H, Nakagawara A, Nagase H.
  • Organizer: 日本癌学会
  • Place of Presentation: YOKOHAMA
• [Presentation] Phosphorylation of NFBD1/MDC1 by plk1 regulates decatenation checkpoint-mediated G2/M transition
  • Author(s): Ando K, Ozaki T, Hirota T, Nakagawara A.
  • Organizer: 日本癌学会
  • Place of Presentation: YOKOHAMA