Identification and functional analysis of novel p53 target genes related to cellular senescence.

• Project/Area Number: 18687012
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Cell biology
• Research Institution: The University of Tokyo
• Principal Investigator: MATSUDA Koichi The University of Tokyo, 医科学研究所, 助教 (90401257)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2008: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2007: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2006: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: p53 / 老化 / 細胞老化 / 遺伝子多型 / 前立腺癌 / 癌抑制遺伝子

Research Abstract

老化関連研究は社会の高齢化に伴い注目度も高まり、老化関連因子が次々と明らかになる等分子レベルでもそのメカニズムが解明されつつある。癌化との関連についても活発に研究が進められ、細胞老化という現象が前癌組織でも観察され、老化が癌化へのバリアーとして機能している可能性が示唆された。さらにマウスでの解析などにより代表的な癌抑制遺伝子であるp53が個体老化及び細胞老化へ関与することが示され、細胞老化誘導がp53の癌抑制機能の一端を担っていると認識されるようになった。
本研究の目的は 1)p53遺伝子導入による発現誘導 2)細胞の継代に伴う遺伝子発現変化 3)癌組織及び前癌組織における遺伝子発現プロファイル 以上3 つのマイクロアレーデータを用いて網羅的な遺伝子スクリーニングを行うことによりp53依存性細胞老化関連遺伝子を単離することである。その結果p53及び細胞老化の過程で発現誘導されかつ前立腺癌組織で顕著に発現が減少している遺伝子としてp53SA1を同定した。p53SA1はプロモーター上のp53結合配列を介してp53によって発現誘導されp53の直接の下流遺伝子である事が明らかとなった。さらにp53SA1を過剰発現させた際に、複数の細胞株において増殖抑制効果を示すとともに、老化のマーカーであるSA-βgal染色陽性細胞が観察された。またp53SA1の発現抑制によっても酸化ストレスによって誘導される細胞老化が抑制されたことより、p53SA1は細胞老化の重要なメディエーターである事が明らかとなった。p53SA1遺伝子上のアミノ酸置換を伴う多型によって、細胞内の局在が膜型と細胞質型とに変化することが確認された。さらに膜型のp53SA1のキャリアーでは前立腺癌の発症が増加する傾向が認められた。また前立腺癌組織において発現を検討した所、顕著な発現抑制が確認され、この発現低下にはp53の変異に加えepigeneticな発現抑制機序が関与していることが示された。以上の結果よりp53SA1は癌組織において老化を誘導することによって癌抑制遺伝子として働く可能性が示唆された。

Research Products

• [Journal Article] XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway (2009)
  • Author(s): Tanikawa C, Furukawa Y, Yoshida N, Arakawa H, Nakamura Y, Matsuda K.
  • Journal Title: Oncogene (In press)
• [Journal Article] Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma (2009)
  • Author(s): Morioka K, Tanikawa C, Ochi K, Daigo Y, Katagiri T, Kawano H, Matsuda K, et al.
  • Journal Title: Cancer Sci. Apr 15
  • NAID: 10027191977
• [Journal Article] A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians (2009)
  • Author(s): Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, Matsuda K, et al.
  • Journal Title: Nat Genet. May;41(5) Pages: 591-5
• [Journal Article] Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE) (2009)
  • Author(s): Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guthridge JM, Matsuda K, et al.
  • Journal Title: Hum Mol Genet. Mar 15;18(6) Pages: 1171-80
• [Journal Article] 大腸癌関連遺伝子の全ゲノム関連解析 (2009)
  • Journal Title: 最新医学 64巻4号
• [Journal Article] A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians (2009)
  • Author(s): Kamatani Y, Wattanapokayakit S, Ochi. H, Kawaguchi T, Takahashi A, Hosono N, Kubo M, Tsunoda T, Kamatani N, Kumada H, Puseenam A, Sum T, Daigo Y. Chavama K. Chantratila W, Naltatinira Y, Matsuda
  • Journal Title: Nat Genet 41(5) Pages: 591-5
  • Peer Reviewed
• [Journal Article] Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE) (2009)
  • Author(s): Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guiluidge JM, Thomas K, Kaufman KM, Ojwang J, Rojas-Villarraga A, Baca V, Orozco L, Rhodes B, Choi CB, Gregersen PK, Merrill JT, James JA, Gaffney PM, Moser KL, Jacob CO, Kimberly RP, Harley JB, Bae SC, Anaya JM, Alarcon-Riquelme ME, Matsuda K Vvse TJ. Nath SR
  • Journal Title: Hum. Mol. Genet 18(6) Pages: 1171-80
  • Peer Reviewed
• [Journal Article] Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21 (2008)
  • Author(s): Tenesa A, Farrington SM, Prendergast JG, Porteous ME, Walker M, Haq N, Matsuda K, et al.
  • Journal Title: Nat Genet. May;40(5) Pages: 631-7
• [Journal Article] Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population (2008)
  • Author(s): Suzuki A, Yamada R, Kochi Y, Sawada T, Okada Y, Matsuda K, et al.
  • Journal Title: Nat Genet. Oct;40(10) Pages: 1224-9
• [Journal Article] Involvement of kinesin family member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis (2008)
  • Author(s): Shimo A, Tanikawa C, Nishidate T, Lin ML, Matsuda K, Park JH, et al.
  • Journal Title: Cancer Sci. Jan;99(1) Pages: 62-70
  • NAID: 10024000927
• [Journal Article] Potential involvement of p53 in ischemia/reperfusion-induced osteonecrosis (2008)
  • Author(s): Okuma C, Kaketa T, Hikita A, Matsuda K, Nakamura M, Nagase Y, et al.
  • Journal Title: J Bone Miner Metab. 26(6) Pages: 576-85
  • NAID: 10024460040
• [Journal Article] A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population (2008)
  • Author(s): Oishi T, Iida A, Otsubo S, Kamatani Y, Usami M, Takei T, Matsuda K, et al.
  • Journal Title: J Hum Genet. 53(2) Pages: 151-62
  • NAID: 10021247900
• [Journal Article] CDC20, a potential cancer therapeutic target, is negatively regulated by p53 (2008)
  • Author(s): Kidokoro T, Tanikawa C, Furukawa Y, Katagiri T, Nakamura Y, Matsuda K
  • Journal Title: Oncogene Mar 6;27(11) Pages: 1562-71
• [Journal Article] Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population (2008)
  • Author(s): Kamatani Y, Matsuda K, Ohishi T, Ohtsubo S, Yamazaki K, Iida A, et al.
  • Journal Title: J Hum Genet. 53(1) Pages: 64-73
  • NAID: 10021247556
• [Journal Article] CDC20, a potential cancer therapeutic target, is negatively regulated by p53 (2008)
  • Author(s): Kidokoro T, Tanikawa C, Furukawa Y, Katagiri T, Nakamura Y, Matsuda
  • Journal Title: Oncogene 27(11) Pages: 1562-71
  • Peer Reviewed
• [Journal Article] Potential involvement of p53 in ischemia/reperfusion-induced osteonecrosis (2008)
  • Author(s): Okuma C, Kaketa T, Hikita A, Matsuda K, Nakamura M, Nagase Y, Oshima Y, Iwasawa M, Nakamura Y, Kurosawa H, Nakamura K, Tanaka S
  • Journal Title: J Bone Miner Metab 26(6) Pages: 576-85
  • NAID: 10024460040
  • Peer Reviewed
• [Journal Article] Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21 (2008)
  • Author(s): Tenesa A. Farrington SM. Prendergest JG, Porteous ME, Wslker M, Haq N, Beenetson RA, Thoodoratou E, Cetnarskyj R, Cartwright N, Semple G, Clark Arl, Reid FJ, Smith LA, Kavoussanakis K. Roessler T. Pharoah PD, Emir S, Schafmayer C, Tape J, Schreiber S, ValzkeN. Schmidt CO, Hanme J, Chang-Claude J, Hoffmeister M. Brenner H, %limning S, Canzian F, Capella G, Moreno V, Deary IJ, Starr JM, Tomlinson IP. Kemp Z, Hiwarth K. Casvajal Cacmona L, Webb E. Broderick P. Vijayakrisiman J. Houlston RS, Rennert G. Ballinger D, Rezak L. Gruber SB, Matsuda K. Kidokoro T, Nekrunnra Y, Zanke BW, Greenwood CM, Rangrej J, Kustra,R Montpetit A. Hudson TJ, Gallinger S. Campbell H, Dunlop MG
  • Journal Title: Nat Genet 40(5) Pages: 631-7
  • Peer Reviewed
• [Journal Article] Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population (2008)
  • Author(s): Suzuki A, Yamada R., Kochi Y, Sawada T, Okada Y, Matsuda K, Kamatani Y, Mori M, Shimane K, Hirabayashi Y, Takahashi A, Tsunoda T, Miyatake A, Kubo M, Kamatani N. Nakamura Y, Yamamoto K
  • Journal Title: Nat Genet 40(10) Pages: 1224-9
  • Peer Reviewed
• [Journal Article] CDC20, a potential cancer therapeutic target, is negatively regulated by p53. (2008)
  • Author(s): T. omohide Kidokoro, et. al.
  • Journal Title: Oncogene 27 Pages: 1562-1571
  • Peer Reviewed
• [Journal Article] Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. (2008)
  • Author(s): Albert Tenesa, et. al.
  • Journal Title: Nature Genetics (in press)(In press)
  • Peer Reviewed
• [Journal Article] A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population. (2008)
  • Author(s): Tetsuya Oishi, et. al.
  • Journal Title: J Hum Genet 53 Pages: 151-162
  • Peer Reviewed
• [Journal Article] Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population. (2008)
  • Author(s): Yoichiro Kamatani, et. al.
  • Journal Title: J Hum Genet 53 Pages: 64-73
  • Peer Reviewed
• [Journal Article] A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction (2007)
  • Author(s): Kubo M, Hata J, Ninomiya T, Matsuda K, Yonemoto K, Nakano T, et al.
  • Journal Title: Nat Genet. Feb;39(2) Pages: 212-7
• [Journal Article] Oncogenic role of KIAA0101 interacting with proliferating cell nuclear antigen in pancreatic cancer (2007)
  • Author(s): Hosokawa M, Takehara A, Matsuda K, Eguchi H, Ohigashi H, Ishikawa O, et al.
  • Journal Title: Cancer Res. Mar 15;67(6) Pages: 2568-76
• [Journal Article] Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction (2007)
  • Author(s): Hata J, Matsuda K, Ninomiya T, Yonemoto K, Matsushita T, Ohnishi Y, et al.
  • Journal Title: Hum Mol Genet. Mar 15;16(6) Pages: 630-9
• [Journal Article] Functional SNP in an Spl-binding site of AGTRLl gene is associated with susceptibility to brain infarction. (2007)
  • Author(s): Jun Hata, et. al.
  • Journal Title: Hum Mol Genet 16 Pages: 630-639
  • Peer Reviewed
• [Presentation] Genome-wide association study identified colorectal cancer susuceptible loci on 11q23, 8q24, and 18q21 in both Caucasian and Japanese population (2008)
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Genome-wide association study identified colorectal cancer susuceptible loci on 11q23, 8q24, and 18q21 in both Caucasian and Japanese population (2008)
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-28
• [Presentation] ゲノムワイド関連解析による大腸癌疾患感受性領域の同定 (2008)
  • Author(s): 松田浩一、城所知秀、久保充明、中村祐輔
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-28
• [Presentation] Genome wide screening of novel p53 target genes and their involvement in tumorigenesis and cellular senescence (2007)
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] Genome wide screening of novel p53 target genes and their involvement in tumorigenesis and cellular senescence. (2007)
  • Author(s): Koichi Matsuda
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] メカニカルストレスに反応して骨量維持に働く新規遺伝子Znt5(Zinc transporter 5)の単離と機能解析 (2007)
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-07-19
• [Presentation] Identification of novel p53-target genes and their physiological roles in tumor suppression and cellular senescence. (2007)
  • Author(s): Koichi Matsuda
  • Organizer: American association of cancer research
  • Place of Presentation: Los angels, USA
  • Year and Date: 2007-04-17
• [Presentation] Identification of novel p53-target genes and their physiological roles in tumor suppression and cellular senescence (2007)
  • Organizer: アメリカ癌学会
  • Place of Presentation: Los Angeles
  • Year and Date: 2007-04-15
• [Presentation] 細胞老化にともなうp53関連遺伝子の発現解析 (2006)
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2006-09-28
• [Presentation] Screening of p53 regulated genes by cDNA microarray and analysis of its expressions in cancer tissue (2006)
  • Organizer: アメリカ癌学会
  • Place of Presentation: Washington, DC
  • Year and Date: 2006-04-02
• [Remarks] 2008.3.31 毎日新聞 「大腸癌疾患感受性遺伝子を同定」
• [Remarks] 2009.5.1 朝日新聞 「慢性B 型肝炎の個人差関連の遺伝子を特定」
• [Remarks] 2009.5.14 読売新聞 「お酒に弱いのに飲酒・喫煙 食道がんリスク190倍」
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/nakamura/main/top.html