Transcribed-ultraconserved regions regulate cellular senescence and proliferation of conlon cancer.

• Project/Area Number: 26713027
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokushima
• Principal Investigator: KUWANO Yuki 徳島大学, 大学院医歯薬学研究部, 助教 (00563454)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥23,530,000 (Direct Cost: ¥18,100,000、Indirect Cost: ¥5,430,000); Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2015: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2014: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 非コードRNA / RNAプロセシング / 大腸がん / 超保存領域 / 癌 / 発現制御 / 遺伝子 / マイクロアレイ / 癌悪性化 / 安定過剰発現細胞

Outline of Final Research Achievements

Ultraconserved regions (UCRs) are >200-bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood.
The transformer 2β (TRA2B) exon 2 has premature stop codons, whereas an exon 2-containing splice variant (TRA2β4) was expressed preferentially in the nuclei of human colon cancer cells. TRA2β4 knockdown stimulated CDKN1A transcription and increased p21, resulting in the appearance of senescent cells. TRA2β4 interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. These results suggest that TRA2β4 may sequester Sp1 from occupying promoters of target genes including CDKN1A, promoting cell growth by interrupting the senescence-related gene expression program.

Research Products

• [Journal Article] Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome (2016)
  • Author(s): Kuwano Y, Nishida K, Akaike Y, Kurokawa K, Nishikawa T, Masuda K, Rokutan K
  • Journal Title: Int J Mol Sci Volume: 17 Issue: 10 Pages: 10-10
  • DOI: 10.3390/ijms17101638
  • NAID: 120006535037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serine/arginine-rich splicing factor 7 regulates p21-dependent growth arrest in colon cancer cells (2016)
  • Author(s): Saijo S, Kuwano Y, Masuda K, Nishikawa T, Rokutan K, Nishida K
  • Journal Title: J Med Invest Volume: 63 Issue: 3.4 Pages: 219-226
  • DOI: 10.2152/jmi.63.219
  • NAID: 130005245836
  • Peer Reviewed / Open Access
• [Journal Article] Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells (2015)
  • Author(s): Kajita K, Kuwano Y, Satake Y, Kano S, Kurokawa K, Akaike Y, Masuda K, Nishida K, Rokutan K
  • Journal Title: Oncogenesis Volume: - Issue: 4 Pages: e213-e213
  • DOI: 10.1038/oncsis.2016.18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3’UTR of BCL2 mRNA. (2015)
  • Author(s): Kuwano Y, Nishida K, Kajita K, Satake Y, Akaike Y, Fujita K, Kano S, Masuda K, Rokutan K.
  • Journal Title: Cell Death Differ. Volume: 22 (5) Issue: 5 Pages: 815-825
  • DOI: 10.1038/cdd.2014.176
  • Peer Reviewed / Open Access
• [Journal Article] Homeodomain-interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ. (2014)
  • Author(s): Akaike Y, Kuwano Y, Nishida K, Kurokawa K, Kajita K, Kano S, Masuda K, Rokutan K.
  • Journal Title: Oncogene. Volume: - Issue: 26 Pages: 3463-3473
  • DOI: 10.1038/onc.2014.278
  • Peer Reviewed / Open Access
• [Journal Article] HuR regulates alternative splicing of the TRA2 β gene in human colon cancer cells under oxidative stress. (2014)
  • Author(s): Akaike Y, Masuda K, Kuwano Y, Nishida K, Kajita K, Kurokawa K, Satake Y, Shoda K, Imoto I, Rokutan K.
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 15 Pages: 2857-73
  • DOI: 10.1128/mcb.00333-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Ultraconserved region-containing transformer 2β4 associates with nucleolin and regulates cellular proliferation. (2017)
  • Author(s): Kuwano Y, Satake Y, Nishikawa T, Fujita M, Saijo S, Nishida K, Rokutan K.
  • Organizer: Protein-RNA Interactions: Keystone symposia
  • Place of Presentation: Banff (Canada)
  • Year and Date: 2017-02-05
  • Int'l Joint Research
• [Presentation] Serine/arginine-richスプライシング因子SRSFを介したエピジェネティック調節機構 (2016)
  • Author(s): 桑野由紀、西田憲生、西川達哉、六反一仁
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県、横浜市)
  • Invited
• [Presentation] Ultraconserved regionを内在するTRA2β4の発現制御と大腸がんの細胞増殖メカニズムの解明 (2016)
  • Author(s): 西川達哉、桑野 由紀、小玉 美幸、西條早希、田中 裕基、板井 美樹、藤田 絹代、西田 憲生、六反 一仁
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県、横浜市)
• [Presentation] Ultraconserved regionを内在するTRA2β4を介した細胞周期調節メカニズムの解析 (2015)
  • Author(s): 小玉美幸、桑野由紀、佐竹譲、狩野静香、藤田絹代、板井美樹、田中裕基、千葉美穂、西田憲生、六反一仁
  • Organizer: 第38回日本分子生物学会
  • Place of Presentation: 神戸ポートアイランド (兵庫県・神戸市)
  • Year and Date: 2015-12-02
• [Presentation] TRA2β4とnucleolinの相互作用を介した大腸癌細胞増殖メカニズムの解明 (2015)
  • Author(s): 佐竹譲、桑野由紀、狩野静香、藤田絹代、板井美樹、田中裕基、西田憲生、六反一仁
  • Organizer: 第38回日本分子生物学会
  • Place of Presentation: 神戸ポートアイランド (兵庫県・神戸市)
  • Year and Date: 2015-12-01
• [Presentation] Ultraconserved region-containing transformer 2β4 inhibits senesces of colon cancer cells. (2015)
  • Author(s): Kuwano Y, Kajita K, Kano S, Satake Y, Fujita M, Itai M, Nishida K, Rokutan K.
  • Organizer: Cell symposia-Human genomics
  • Place of Presentation: Singapore (Singapore)
  • Year and Date: 2015-11-08
  • Int'l Joint Research
• [Presentation] 新規非コードRNA TRA2β4を介した大腸がん悪性化の分子基盤 (2015)
  • Author(s): 桑野由紀、佐竹譲、狩野静香、藤田絹代、西田憲生、六反一仁
  • Organizer: 第10回臨床ストレス応答学会
  • Place of Presentation: 東京農工大（東京都・小金井市）
  • Year and Date: 2015-11-06
• [Presentation] ストレス応答性マイクロRNAを介した遺伝子発現調節 (2015)
  • Author(s): 桑野由紀、六反一仁
  • Organizer: 第56回日本心身医学会学術総会ならびに学術講演会
  • Place of Presentation: タワーホール船橋（東京都・江戸川区）
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] 非コードRNA(T-UCR)を介した大腸がんの細胞増殖メカニズムの検討 (2014)
  • Author(s): 桑野由紀、梶田啓介、佐竹謙、狩野静香、藤田絹代、板井美樹、西田憲生、成戸卓也、六反一仁
  • Organizer: 第9回臨床ストレス応答学会
  • Place of Presentation: マスカットキューブ （岡山県、岡山市）
  • Year and Date: 2014-11-02
• [Presentation] Analysis of functional transcribed-ultraconserved regions of SR protein family. (2014)
  • Author(s): Kano S, Nishida K, Satake Y, Fujita K, Itai M, Naruto T, Masuda K, Kuwano Y, Rokutan K.
  • Organizer: Cell symposia-Regulatroy RNAs
  • Place of Presentation: Berkeley, California, U.S.A
  • Year and Date: 2014-10-20
• [Presentation] Transformer 2b and miR-204 regulate cell death through competitive binding to 3’UTR of BCL2 mRNA. (2014)
  • Author(s): Kuwano Y, Satake S, Kano S, Fujita M, Itai M, Nishida K, Naruto T, Masuda K, Rokutan K.
  • Organizer: Cell symposia-Regulatroy RNAs
  • Place of Presentation: Berkeley, California, U.S.A
  • Year and Date: 2014-10-19