KLF4

KLF4
PDBに登録されている構造
PDBオルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧

2WBS, 2WBU, 4M9E

識別子
記号KLF4, EZF, GKLF, Kruppel-like factor 4 (gut), Kruppel like factor 4
外部IDOMIM: 602253 MGI: 1342287 HomoloGene: 3123 GeneCards: KLF4
遺伝子の位置 (ヒト)
9番染色体 (ヒト)
染色体9番染色体 (ヒト)[1]
9番染色体 (ヒト)
KLF4遺伝子の位置
KLF4遺伝子の位置
バンドデータ無し開始点107,484,852 bp[1]
終点107,490,482 bp[1]
遺伝子の位置 (マウス)
4番染色体 (マウス)
染色体4番染色体 (マウス)[2]
4番染色体 (マウス)
KLF4遺伝子の位置
KLF4遺伝子の位置
バンドデータ無し開始点55,527,143 bp[2]
終点55,532,466 bp[2]
RNA発現パターン


さらなる参照発現データ
遺伝子オントロジー
分子機能• DNA結合
• sequence-specific DNA binding
• beta-catenin binding
• phosphatidylinositol 3-kinase regulator activity
• DNA-binding transcription factor activity
• zinc ion binding
• DNA-binding transcription activator activity, RNA polymerase II-specific
• 転写因子結合
• cis-regulatory region sequence-specific DNA binding
• 金属イオン結合
• RNA polymerase II sequence-specific DNA-binding transcription factor recruiting activity
• 血漿タンパク結合
• 核酸結合
• 二本鎖DNA結合
• promoter-specific chromatin binding
• RNA polymerase II cis-regulatory region sequence-specific DNA binding
• DNA-binding transcription factor activity, RNA polymerase II-specific
• transcription coregulator binding
• ヒストンデアセチラーゼ結合
細胞の構成要素• 細胞質
• transcription regulator complex
• 核質
• クロマチン
• 細胞核
生物学的プロセス• negative regulation of chemokine (C-X-C motif) ligand 2 production
• epidermal cell differentiation
• cellular response to retinoic acid
• negative regulation of protein kinase B signaling
• negative regulation of muscle hyperplasia
• negative regulation of smooth muscle cell proliferation
• positive regulation of protein metabolic process
• negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
• regulation of axon regeneration
• cellular response to peptide
• regulation of transcription, DNA-templated
• positive regulation of hemoglobin biosynthetic process
• response to retinoic acid
• somatic stem cell population maintenance
• cellular response to laminar fluid shear stress
• regulation of transcription by RNA polymerase II
• 細胞分化
• epidermis morphogenesis
• positive regulation of nitric oxide biosynthetic process
• cellular response to growth factor stimulus
• cellular response to organic cyclic compound
• post-embryonic hemopoiesis
• negative regulation of transcription by RNA polymerase II
• transcription by RNA polymerase II
• 有機物への反応
• 遺伝子発現の負の調節
• negative regulation of response to cytokine stimulus
• transcription, DNA-templated
• negative regulation of DNA-binding transcription factor activity
• negative regulation of phosphatidylinositol 3-kinase signaling
• stem cell population maintenance
• negative regulation of cell migration involved in sprouting angiogenesis
• positive regulation of gene expression
• negative regulation of cell migration
• regulation of cell population proliferation
• post-embryonic camera-type eye development
• regulation of phosphatidylinositol 3-kinase activity
• positive regulation of telomerase activity
• canonical Wnt signaling pathway
• negative regulation of ERK1 and ERK2 cascade
• regulation of cell differentiation
• mesodermal cell fate determination
• negative regulation of heterotypic cell-cell adhesion
• negative regulation of transcription, DNA-templated
• negative regulation of NF-kappaB transcription factor activity
• cellular response to cycloheximide
• negative regulation of inflammatory response
• 脂肪細胞の分化
• positive regulation of transcription by RNA polymerase II
• negative regulation of cell population proliferation
• cellular response to hydrogen peroxide
• negative regulation of leukocyte adhesion to arterial endothelial cell
• positive regulation of core promoter binding
• cellular response to leukemia inhibitory factor
• negative regulation of angiogenesis
• pri-miRNA transcription by RNA polymerase II
• negative regulation of G1/S transition of mitotic cell cycle
• positive regulation of transcription, DNA-templated
• positive regulation of sprouting angiogenesis
出典:Amigo / QuickGO
オルソログ
種ヒトマウス
Entrez

9314

16600

Ensembl

ENSG00000136826

ENSMUSG00000003032

UniProt

O43474

Q60793

RefSeq
(mRNA)

NM_001314052
NM_004235

NM_010637

RefSeq
(タンパク質)

NP_001300981
NP_004226

NP_034767

場所
(UCSC)		Chr 9: 107.48 – 107.49 MbChr 9: 55.53 – 55.53 Mb
PubMed検索[3][4]
ウィキデータ
閲覧/編集 ヒト閲覧/編集 マウス

KLF4（Kruppel like factor 4）は、ジンクフィンガー型転写因子であるKLFファミリー（英語版）の一員である。KLFファミリーはSp1様転写因子とともにSp1-like/KLFファミリーを構成する転写因子群である[5][6][7]。KLF4は細胞増殖、分化、アポトーシス、体細胞のリプログラミングの調節に関与している。また、KLF4は大腸がんなど特定のがんでがん抑制因子として機能することを示唆する証拠が得られている[8]。KLF4のC末端には3つのC2H2型ジンクフィンガーが存在し、これらはKLF2（英語版）と密接な関係にある[6]。また、2つの核局在配列が存在し、KLF4を細胞核へ局在させるシグナルとなっている[9]。胚性幹細胞では、KLF4は幹細胞性の良い指標となることが実証されている。このことは、間葉系幹細胞にも当てはまる。

ヒトのKLF4タンパク質はKLF4遺伝子にコードされ、513アミノ酸からなり、約55 kDaと推定される[10]。KLF4遺伝子はチンパンジー、アカゲザル、イヌ、ウシ、マウス、ラット、ニワトリ、ゼブラフィッシュの間で保存されている[10]。KLF4は1996年に初めて同定された[11]。

相互作用

KLF4はN末端領域を介してp300/CBPコアクチベーターファミリーと相互作用し、転写を活性化することができる[12][13][14][15]。一方、KLF4による転写抑制は、アクチベーターの標的DNAへの結合に対しKLF4が競合することで行われる[16][17][18][19]。

KLF4はテロメラーゼの酵素サブユニット（TERT）のプロモーター領域に存在することも示されており、そこではβ-カテニンと複合体を形成している。KLF4はTERTのプロモーター領域へのβ-カテニンの蓄積に必要であるが、β-カテニンが存在しない場合にはTERTの発現を促進することはできない[20]。

機能

KLF4は多様な機能を持ち、その機能の一部は見かけ上矛盾したようなものであること、そして何より人工多能性幹細胞（iPS細胞）の誘導に必要不可欠な4つの因子のうちの1つとして重要な役割を果たしていることが発見されたことにより、近年大きな関心を集めている[21][22]。KLF4は非分裂細胞で高度に発現しており、その過剰発現は細胞周期の停止を誘導する[11][23][24][25][26]。KLF4はDNAが損傷した際の細胞分裂の阻害に特に重要である[23][25][26][27]。また、KLF4は中心体や染色体の数の調節（遺伝的安定性）や[28][29][30]、細胞の生存の促進にも重要である[31][31][32][33][34][35][36]。しかしながら、KLF4は特定の条件下では細胞生存促進から細胞死促進へ、その機能を切り替えている可能性が一部の研究で明らかにされている[35][37][38][39]。

KLF4は腸管上皮において細胞分裂を行っていない細胞や終末分化した細胞で発現しており、腸管上皮の恒常性（さまざまな腸管上皮細胞種の終末分化と適切な局在）の調節に重要な役割を果たしている[40][41][42][43]。腸管上皮においては、KLF4は分化を調節するWntシグナル経路の遺伝子の重要な調節因子である[43]。

KLF4は他にもさまざまな組織や器官で発現している。角膜ではKLF4は上皮バリア機能に必要であり[44][45]、角膜の恒常性の維持に必要な遺伝子の調節因子である[46]。皮膚でも透過バリア機能の構築に必要であり[47][48][49]、骨や歯の組織では正常な骨格の発達を調節している[50][51][52][53]。マウスの生殖器の上皮細胞でも発現しており[54]、オスでは適切な精子形成に重要である[55][56][57]。血管内皮細胞では炎症刺激に応答した血管漏出の防止に重要であり[58][59]、血液細胞では炎症応答や細胞分化[60][61][62][63]、増殖[63][64]を媒介している。腎臓に関しては、in vitroにおける胚性幹細胞やiPS細胞の腎臓系統への分化に関与しており[65]、KLF4の調節異常はいくつかの腎臓疾患と関連している[66][67][68]。

疾患における役割

KLF4の疾患における役割は状況依存的であり、状況によって正反対の役割を果たす可能性があることが示されている。

KLF4は抗腫瘍形成因子であり、大腸がん[69]、胃がん[70]、食道扁平上皮がん[32]、小腸がん[71]、前立腺がん[72]、膀胱がん[73]、肺がん[74]など、ヒトのさまざまながんにおいて発現が喪失していることが多い。しかしながら、一部のがんではKLF4が腫瘍のプロモーションに関与している可能性があり、口腔扁平上皮がん[75]や原発性乳管がん[76]などではKLF4の発現は増大している。また、皮膚でのKLF4の過剰発現は過形成や異形成を引き起こし[77]、扁平上皮がんの発生につながる[78]。同様の知見は食道上皮でも得られており、マウスではKLF4の過剰発現は炎症の増大を引き起こし、最終的には食道扁平上皮がんの発生につながる[79]。

上皮間葉転換（EMT）におけるKLF4の役割に関しても議論がある。膵臓がん[80][81][82]、頭頸部がん[83]、子宮体がん[84]、上咽頭がん（英語版）[85]、前立腺がん[86]、非小細胞肺がん[87]では、KLF4はがん細胞の幹細胞性の維持や促進を刺激することが示されている。一方で、前立腺がん[88]や膵臓がん[89]などKLF4がEMTを促進することが示されている系においても、TGF-β誘導性のEMT条件下ではKLF4がEMTを抑制することが示されている。さらに、皮膚がん[90]、乳がん[35]、肺がん[91]、シスプラチン抵抗性上咽頭がん[92]では、KLF4がEMTを抑制することが示されている。

KLF4はいくつかの血管疾患で重要な役割を果たしており、マクロファージの極性化[93]やアテローム性動脈硬化におけるプラーク形成[94][95][96]を制御することで血管の炎症を調節することが示されている。KLF4は、抗アテローム性因子であるアポリポプロテインEをアップレギュレーションする[95]。また、KLF4は血管新生の調節にも関与している。KLF4はNOTCH1（英語版）の活性を調節することで血管新生を抑制している可能性がある一方で、中枢神経系ではKLF4の過剰発現は血管の異形成を引き起こす[97]。

マウスのマクロファージ[18]、食道上皮[79]、そして薬剤起因性大腸炎[98]などにおいては、KLF4がNF-κB依存的な炎症経路を介して炎症を促進している可能性が示されている。しかしながら、炎症促進刺激に応答した内皮細胞などではKLF4が炎症シグナルの活性化を抑制ている可能性が示されている[58]。

KLF4はDNA損傷に対する細胞応答に必要不可欠である。KLF4はガンマ線照射によるDNA損傷後の有糸分裂への進行の阻害に必要であり[25][26]、DNA修復機構を促進し、照射細胞のプログラム細胞死（アポトーシス）を防ぐ[31][33][34]。腸管上皮特異的にKLF4を欠失したマウスではガンマ線照射後の腸管上皮の再生が行われず、致死率が増加することから、この応答におけるKLF4の重要性がin vivoで示されている[34]。

幹細胞における重要性

高橋和利と山中伸弥によって、KLF4がマウスの胎児や成体の線維芽細胞を多能性幹細胞（iPS細胞）へ誘導するために必要な4つの因子のうちの1つ（他の3つはOct3/4、Sox2、c-Myc）であることが同定された[22]。この4つの因子はヒトの成人の線維芽細胞に対しても当てはまることが発見されている[21]。この2006年の発見以降現在に至るまで、幹細胞やその誘導に関する臨床的に重要な研究は劇的に増加した。一方で、幹細胞におけるin vivoでのKLF4の機能研究は比較的少数である。腸管幹細胞の一集団であるBmi1+幹細胞の分裂は通常は遅く、放射線照射に対する抵抗性を持ち、照射損傷後の腸管上皮の再生を担う集団であることが知られている[99]。ガンマ線照射によるDNA損傷後の腸管では、KLF4はBmi1+幹細胞の運命、そしてBmi1+幹細胞由来の細胞系統の発生を調節することで腸管の再生を調節している[36]。

出典

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136826 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003032 - Ensembl, May 2017
  3. ^ Human PubMed Reference:
  4. ^ Mouse PubMed Reference:
  5. ^ “Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer”. Journal of Cellular Physiology 188 (2): 143–60. (August 2001). doi:10.1002/jcp.1111. PMID 11424081. 
  6. ^ a b “The biology of the mammalian Krüppel-like family of transcription factors”. The International Journal of Biochemistry & Cell Biology 32 (11–12): 1103–21. (November 2000). doi:10.1016/s1357-2725(00)00059-5. PMC 2754176. PMID 11137451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754176/. 
  7. ^ “Sp1- and Krüppel-like transcription factors”. Genome Biology 4 (2): 206. (2003). doi:10.1186/gb-2003-4-2-206. PMC 151296. PMID 12620113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC151296/. 
  8. ^ “Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts”. Molecular Cancer 12: 89. (August 2013). doi:10.1186/1476-4598-12-89. PMC 3750599. PMID 23919723. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750599/. 
  9. ^ “Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins”. The Journal of Biological Chemistry 272 (29): 18504–7. (July 1997). doi:10.1074/jbc.272.29.18504. PMC 2268085. PMID 9218496. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268085/. 
  10. ^ a b “Entrez Gene: KLF4 Kruppel-like factor 4 (gut)”. 2022年10月16日閲覧。
  11. ^ a b “Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest”. The Journal of Biological Chemistry 271 (33): 20009–17. (August 1996). doi:10.1074/jbc.271.33.20009. PMC 2330254. PMID 8702718. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330254/. 
  12. ^ “A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells”. The Journal of Biological Chemistry 271 (49): 31384–90. (December 1996). doi:10.1074/jbc.271.49.31384. PMID 8940147. 
  13. ^ “Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction”. Nucleic Acids Research 28 (5): 1106–13. (March 2000). doi:10.1093/nar/28.5.1106. PMC 102607. PMID 10666450. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC102607/. 
  14. ^ “Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation”. The Journal of Biological Chemistry 282 (47): 33994–4002. (November 2007). doi:10.1074/jbc.M701847200. PMID 17908689. 
  15. ^ “Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction”. Nucleic Acids Research 28 (5): 1106–13. (March 2000). doi:10.1093/nar/28.5.1106. PMC 102607. PMID 10666450. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC102607/. 
  16. ^ “The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion”. The Journal of Biological Chemistry 273 (28): 17917–25. (July 1998). doi:10.1074/jbc.273.28.17917. PMC 2275057. PMID 9651398. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275057/. 
  17. ^ “Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements”. The Journal of Biological Chemistry 279 (10): 8684–93. (March 2004). doi:10.1074/jbc.M308278200. PMID 14670968. 
  18. ^ a b “Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages”. The Journal of Biological Chemistry 280 (46): 38247–58. (November 2005). doi:10.1074/jbc.M509378200. PMID 16169848. 
  19. ^ “Loss of Krüppel-like factor 4 expression contributes to Sp1 overexpression and human gastric cancer development and progression”. Clinical Cancer Research 12 (21): 6395–402. (November 2006). doi:10.1158/1078-0432.CCR-06-1034. PMID 17085651. 
  20. ^ “Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells”. Science 336 (6088): 1549–54. (June 2012). Bibcode: 2012Sci...336.1549H. doi:10.1126/science.1218370. PMID 22723415. 
  21. ^ a b “Induction of pluripotent stem cells from adult human fibroblasts by defined factors”. Cell 131 (5): 861–72. (November 2007). doi:10.1016/j.cell.2007.11.019. hdl:2433/49782. PMID 18035408. 
  22. ^ a b “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors”. Cell 126 (4): 663–76. (August 2006). doi:10.1016/j.cell.2006.07.024. hdl:2433/159777. PMID 16904174. 
  23. ^ a b “Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle”. The Journal of Biological Chemistry 276 (32): 30423–8. (August 2001). doi:10.1074/jbc.M101194200. PMC 2330258. PMID 11390382. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330258/. 
  24. ^ “Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity”. Oncogene 22 (22): 3424–30. (May 2003). doi:10.1038/sj.onc.1206413. PMC 2275074. PMID 12776194. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275074/. 
  25. ^ a b c “Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage”. The Journal of Biological Chemistry 279 (6): 5035–41. (February 2004). doi:10.1074/jbc.M307631200. PMC 1262649. PMID 14627709. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1262649/. 
  26. ^ a b c “Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage”. The Journal of Biological Chemistry 278 (4): 2101–5. (January 2003). doi:10.1074/jbc.M211027200. PMC 2229830. PMID 12427745. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229830/. 
  27. ^ “Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage”. Oncogene 24 (25): 4017–25. (June 2005). doi:10.1038/sj.onc.1208576. PMC 1626272. PMID 15806166. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1626272/. 
  28. ^ “Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts”. Molecular Cancer 12: 89. (August 2013). doi:10.1186/1476-4598-12-89. PMC 3750599. PMID 23919723. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750599/. 
  29. ^ “Mouse embryonic fibroblasts null for the Krüppel-like factor 4 gene are genetically unstable”. Oncogene 28 (9): 1197–205. (March 2009). doi:10.1038/onc.2008.465. PMC 2667867. PMID 19137014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667867/. 
  30. ^ “KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis”. Molecular Cancer Research 14 (4): 385–96. (April 2016). doi:10.1158/1541-7786.MCR-15-0410. PMC 4834227. PMID 26839262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834227/. 
  31. ^ a b c “The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene”. Nature Cell Biology 7 (11): 1074–82. (November 2005). doi:10.1038/ncb1314. hdl:1874/17842. PMID 16244670. 
  32. ^ a b “KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells”. Cancer Biology & Therapy 4 (11): 1216–21. (November 2005). doi:10.4161/cbt.4.11.2090. PMID 16357509. 
  33. ^ a b “The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology”. BioEssays 29 (6): 549–57. (June 2007). doi:10.1002/bies.20581. PMC 2211634. PMID 17508399. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211634/. 
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