Analysis of functional regulation of PGMRC1

• Project/Area Number: 15K07011
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Keio University
• Principal Investigator: Kabe Yasuaki 慶應義塾大学, 医学部(信濃町), 講師 (20397037)
• Co-Investigator(Renkei-kenkyūsha): UCHIDA Tsuyoshi 北海道大学, 理学部, 准教授 (30343742)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヘム / がん増殖 / 構造生物科学 / 金属タンパク質 / 結晶構造解析 / 癌

Outline of Final Research Achievements

Progesterone receptor membrane component 1 (PGRMC1) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown. Crystallographic analyses revealed that PGRMC1 forms a stable dimer through stacking interactions of two protruding haem molecules. The haem iron is five-coordinated by Tyr113. Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs. This study demonstrates protein dimerization via haem-haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.

Research Products

• [Int'l Joint Research] University of Bari(Italy)
• [Int'l Joint Research] University of Southern California,(米国)
• [Journal Article] Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival (2018)
  • Author(s): Shiota M, Naya M, Yamamoto T, Hishiki T, Tani T, Takahashi H, Kubo A, Koike D, Itoh M, Ohmura M, Kabe Y, Sugiura Y, Hiraoka N, Morikawa T, Takubo K, Suina K, Nagashima H, Sampetrean O, Nagano O, Saya H, Yamazoe S, Watanabe H, Suematsu M
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1561-1561
  • DOI: 10.1038/s41467-018-03899-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quiescence of adult oligodendrocyte precursor cells requires thyroid hormone and hypoxia to activate Runx1. (2017)
  • Author(s): Tokumoto Y, Tamaki S, Kabe Y, Takubo K, Suematsu M
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1019-1019
  • DOI: 10.1038/s41598-017-01023-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. (2017)
  • Author(s): Lai KK, Kweon SM, Chi F, Hwang E, Kabe Y, Higashiyama R, Qin L, Yan R, Wu RP, Fujii N, French S, Xu J, Wang JY, Murali R, Mishra L, Lee JS, Ntambi JM, Tsukamoto H.
  • Journal Title: Gastroenterology Volume: S0016-5085 Issue: 6 Pages: 300081-300081
  • DOI: 10.1053/j.gastro.2017.01.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism (2017)
  • Author(s): Nishimoto, K., Koga, M., Seki, T., Oki, K., Gomez-Sanchez, E.P., Gomez-Sanchez, C.E., Naruse, M., Sakaguchi, T., Morita, S., Kosaka, T., Oya, M., Ogishima, T., Yasuda, M., Suematsu, M., Kabe, T., Omura, M., Nishikawa, T., Mukai, K.
  • Journal Title: Mol. Cell. Endocrinol. Volume: 441 Pages: 124-133
  • DOI: 10.1016/j.mce.2016.10.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism. (2017)
  • Author(s): Tamura A, Nishimoto K, Seki T, Matsuzawa Y, Saito J, Omura M, Gomez-Sanchez CE, Makita K, Matsui S, Moriya N, Inoue A, Nagata M, Sasano H, Nakamura Y, Yamazaki Y, Kabe Y, Mukai K, Kosaka T, Oya M, Suematsu S, Nishikawa T.
  • Journal Title: Mol Cell Endocrinol. Volume: 441 Pages: 134-139
  • DOI: 10.1016/j.mce.2016.07.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CO応答性ヘムタンパク質PGRMC1による悪性腫瘍の増殖と薬剤耐性のメカニズムの解明 (2017)
  • Author(s): 加部泰明、末松誠
  • Journal Title: 生化学 Volume: 89 Pages: 88-88
  • NAID: 40021439299
• [Journal Article] Disorganized steroidogenesis in adrenocortical carcinoma, a case study (2017)
  • Author(s): Uchida, T., Nishimoto, K., Fukumura, Y., Asahina, M., Goto, H., Kawano, Y., Shimizu, F., Tsujimura, A., Seki, T., Mukai, K., Kabe, Y., Suematsu, M., Gomez-Sanchez, C.E., Yao, T., Horie, S., Watada, H.
  • Journal Title: Endocr. Pathol. Volume: 28 Issue: 1 Pages: 27-35
  • DOI: 10.1007/s12022-016-9441-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1) are two different proteins: Proofs by fluorescent labeling and binding of sigma-2 receptor ligands to PGRMC1. (2016)
  • Author(s): Pati ML, Groza D, Riganti C, Kopecka J, Niso M, Berardi F, Hager S, Heffeter P, Hirai M, Tsugawa H, Kabe Y, Suematsu M, Abate C.
  • Journal Title: Pharmacological Research Volume: 117 Pages: 67-71
  • DOI: 10.1016/j.phrs.2016.12.023
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cystathionine beta-synthase and PGRMC1 as CO sensors. (2016)
  • Author(s): Kabe Y, Yamamoto T, Kajimura M, Sugiura Y, Koike I, Ohmura M, Nakamura T, Tokumoto Y, Tsugawa H, Handa H, Kobayashi T, and Suematsu M.
  • Journal Title: Free Radical Biology & Medicine Volume: 99 Pages: 333-344
  • DOI: 10.1016/j.freeradbiomed.2016.08.025
  • Peer Reviewed / Open Access
• [Journal Article] Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation. (2016)
  • Author(s): Nishimoto K, Seki T, Hayashi Y, Mikami S, Al-Eyd G, Nakagawa K, Morita S, Kosaka T, Oya M, Mitani F, Suematsu M, Kabe Y, Mukai K.
  • Journal Title: Int J Endocrinol. Volume: 2016 Pages: 7834356-7834356
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis. (2016)
  • Author(s): Takeshita M, Kuno A, Suzuki K, Matsuda A, Shimazaki H, Nakagawa T, Otomo Y, Kabe Y, Suematsu M, Narimatsu H, Takeuchi T.
  • Journal Title: Arthritis Res Ther. Volume: 18 Issue: 1 Pages: 112-112
  • DOI: 10.1186/s13075-016-1013-2
  • Peer Reviewed / Open Access
• [Journal Article] Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. (2016)
  • Author(s): Kabe Y, Nakane T, Koike I, Yamamoto T, Sugiura Y, Harada E, Sugase K, Shimamura T, Ohmura M, Muraoka K, Yamamoto A, Uchida T, Iwata S, Yamaguchi Y, Krayukhina E, Noda M, Handa H, Ishimori K, Uchiyama S, Kobayashi T, Suematsu M.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11030-11030
  • DOI: 10.1038/ncomms11030
  • NAID: 130007529314
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CO-CBS-H2 S Axis: From Vascular Mediator to Cancer Regulator. (2016)
  • Author(s): Suematsu M, Nakamura T, Tokumoto Y, Yamamoto T, Kajimura M, Kabe Y.
  • Journal Title: Microcirculation Volume: 23 Issue: 3 Pages: 183-190
  • DOI: 10.1111/micc.12253
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C. (2015)
  • Author(s): Masuda K, Chiyoda T, Sugiyama N, Segura-Cabrera A, Kabe Y, Ueki A, Banno K, Suematsu M, Aoki D, Ishihama Y, Saya H, Kuninaka S
  • Journal Title: PLoS One Volume: 10 Issue: 2 Pages: 1-22
  • DOI: 10.1371/journal.pone.0118662
  • Peer Reviewed / Open Access
• [Journal Article] Impacts of CD44 knockdown in cancer cells on tumor and host metabolic systems revealed by quantitative imaging mass spectrometry. (2014)
  • Author(s): Ohmura M, Hishiki T, Yamamoto T, Nakanishi T, Kubo A, Tsuchihashi K, Tamada M, Toue S, Kabe Y, Saya H and Suematsu M
  • Journal Title: Nitric Oxide Volume: pii: S1089-8603 Pages: 495-499
  • DOI: 10.1016/j.niox.2014.11.005
  • Peer Reviewed / Open Access
• [Presentation] ヘム含有受容体PGRMC1の構造と機能 (2017)
  • Author(s): 加部泰明
  • Organizer: 第41回日本鉄バイオサイエンス学会学術集会
  • Invited
• [Presentation] 新規ガス受容体PGRMC1の構造的機能制御の解明 (2016)
  • Author(s): 加部泰明
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] 新規ガス受容体PGRMC1の構造的機能制御の解明 (2016)
  • Author(s): 加部泰明
  • Organizer: 日本プロテオーム学会2016年大会
  • Place of Presentation: 北里大学白金キャンパス
  • Year and Date: 2016-07-27
• [Presentation] 肝炎保護成分グリチルリチンの新規受容体探索と生理機能の解明 (2015)
  • Author(s): 加部泰明
  • Organizer: 第22回肝細胞研究会
  • Place of Presentation: 米子コンベンションセンター（鳥取県米子市）
  • Year and Date: 2015-06-04
  • Invited