FOXM1

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Forkhead box M1

Rendering based on PDB 3G73.
有效结构
PDB 直系同源检索:PDBe, RCSB
标识
代号 FOXM1; FKHL16; FOXM1B; HFH-11; HFH11; HNF-3; INS-1; MPHOSPH2; MPP-2; MPP2; PIG29; TGT3; TRIDENT
扩展标识 遗传学602341 鼠基因1347487 同源基因7318 GeneCards: FOXM1 Gene
RNA表达模式
PBB GE FOXM1 202580 x at tn.png
更多表达数据
直系同源体
物种 人类 鼠类
Entrez 2305 14235
Ensembl ENSG00000111206 ENSMUSG00000001517
UniProt Q08050 O08696
mRNA序列 NM_001243088 NM_008021
蛋白序列 NP_001230017 NP_032047
基因位置 Chr 12:
2.97 – 2.99 Mb
Chr 6:
128.36 – 128.38 Mb
PubMed查询 [1] [2]

FOXM1(Forkhead box protein M1)[1]是一种转录因子蛋白质,有关调节细胞周期的重要作用。当FOXM1从小鼠中去除后,幼鼠在出生后不久因心臟衰竭而死亡,由于心肌细胞和肝细胞多倍体的发展[2]。研究显示了FOXM1对染色体偏析基因组稳定性有重大作用。FOXM1因子失调表达了会造成异常的细胞增殖,导致引发癌症[3][4][5][6][7][8][9]

2010年度分子[编辑]

分子细胞生物学及生物技术方案暨研究国际协会(简称为ISMCBBPR)已将FOXM1评为2010年的年度之重要分子。ISMCBBPR之所以选择FOXM1,乃因为看中其在作为癌症治疗靶点上的无限潜力。去年,美国的《癌症研究》(Cancer Research)杂志网站上曾发表了一篇关于英国伦敦大学玛丽皇后学院的研究人员阐述了FOXM1的过度表现如何破坏细胞周期的稳定之文章[10][11][12][13]。从FOXM1的异常上调,进而使细胞陷入基因组的不稳定,随后使得细胞受到如DNA上的损伤,检查点(如p53或p16)被摧毁,以致受损的细胞也能增殖,因而累积了启动癌症所需的遗传突变基因[5][14][15][16][17]

癌前干细胞的标记[编辑]

过表达FOXM1引发癌前细胞疯狂生长导致癌症.
FOXM1的癌症引发机制

在2002年,FOXM1首次被贴上癌蛋白的标签[18]。从此,研究人员将FOXM1的过度表达与肺癌、肝癌、乳腺癌、脑癌及很多其他癌症联系在一起[19][20][21][22][23][24][25][26]。然而,当时的研究人员并不清楚蛋白的过度表达是如何促进癌症的发展,这也阻碍了癌症疗法上的进展与开发。为了更好地了解这过程,伦敦大学玛丽皇后学院临床及诊断口腔科学中心的讲师所领导的研究小组在正常人口腔上皮干细胞中使FOXM1过度表达,进而诱导细胞进入癌变前期细胞增生的阶段[27][28][29][30][31]。通过这个实验,发现FOXM1干扰了干细胞的生长周期及其分裂。正常水平的FOXM1控制了细胞的生长。当细胞定期分裂时,FOXM1也协调了遗传物质分配到两个子细胞中。当FOXM1过度表达时,该蛋白丧失了对细胞生长的控制,使得细胞疯狂生长。因此,FOXM1的表达成为了癌症测试和预防药物开发的重点。但是去除该蛋白的方法并不是一个最理想的选择,因为它是正常器官在发育上为不可或缺之一的蛋白。过去的研究发现,当FOXM1从小鼠中去除后,幼鼠在出生后不久因心脏衰竭而死亡。

臨床益處[编辑]

qMIDS 恶性肿瘤定量指标诊断系统.
qMIDS 基因測試[32]

研究人员已经表明了FOXM1基因过度表达会诱发干细胞异常增殖,故引发了癌症病变[27][33][34][35][36]。因此,目前专家认为FOXM1作为癌症生物标志物具有潜力在多种癌症的临床诊断上带来革命性的变化[37]

目前罹患口腔癌症的患者日益增加。全球口腔癌患者每年超过50万人。根据世界卫生组织的预测在2030年预计将会有100万人罹患口腔癌。吸烟、咀嚼烟草[5]槟榔、喝酒过量都是口腔癌的致病因素。很多癌症在晚期才会出现症状,晚期治疗后的复发率非常高。如果在早期诊断,90%的癌症都可以治愈。迫切需要的是一种灵敏的诊断方法以提高初期诊断癌症的能力,让口腔癌病人能得以争取最早的发现、方能提高存活率和治愈率。

命名为定量恶性肿瘤指数诊断系统qMIDS[38] 目前已发展为一种实用的,敏感的和定量分子的诊断测试. 这是基于FOXM1在患者口腔,皮肤或外阴病变的初期癌症之检测和预测患癌症的风险上的测试。该测试声称可以检测初期口腔或头部和颈部癌症上的准确率,约高达91-94%[39]。再加上适当的治疗(手术)为初期口腔癌的检测奠定了极高的治愈率。此测试可避免后期检测所降低的存活率(晚期发现肿瘤导致小于20%存活率)。这个测试是目前正在积极进行中的临床试验。

许多正在开发的抗肿瘤化合物都以FOXM1为靶点,唯迄今仍未进入临床试验的阶段。且原型药物目前也正在积极研究中。

外部链接[编辑]

参考列表[编辑]

  1. ^ Entrez Gene: FOXM1 forkhead box M1. 
  2. ^ Wierstra I, Alves J. FOXM1, a typical proliferation-associated transcription factor. Biol. Chem. 2007-12, 388 (12): 1257–74. doi:10.1515/BC.2007.159. PMID 18020943. 
  3. ^ Laoukili J, Kooistra MR, Brás A, et al.. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat. Cell Biol. 2005-02, 7 (2): 126–36. doi:10.1038/ncb1217. PMID 15654331. 
  4. ^ Teh M-T, Gemenetzidis E, Chaplin T, Young BD, Philpott MP. Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes. Molecular Cancer. 2010, 9: 45. doi:10.1186/1476-4598-9-45. PMC 2907729. PMID 20187950. 
  5. ^ 5.0 5.1 5.2 Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, Sugden D, Thurlow JK, Cheong SC, Teo SH, Wan H, Waseem A, Parkinson EK, Fortune F, Teh MT. FOXM1 Upregulation Is an Early Event in Human Squamous Cell Carcinoma and it Is Enhanced by Nicotine during Malignant Transformation. (编) Jin, Dong-Yan. PLoS ONE. 2009, 4 (3): e4849. doi:10.1371/journal.pone.0004849. PMC 2654098. PMID 19287496. 
  6. ^ Press release in The Times Online: http://www.timesonline.co.uk/tol/life_and_style/health/article6143744.ece
  7. ^ Press release in Medical Research Council (MRC) UK: http://www.timesonline.co.uk/tol/life_and_style/health/article6143744.ece
  8. ^ Press release in National Health Service (NHS): http://www.nhs.uk/news/2009/04April/Pages/NicotineGumCancer.aspx
  9. ^ Press release in Fox News: http://www.foxnews.com/story/0,2933,517415,00.html
  10. ^ Vincent Shen. 2010 Molecule of the Year. BioTechniques. 
  11. ^ Molecule of the Year 2010: http://ismcbbpr.synthasite.com/molyearnews.php
  12. ^ Queen Mary University of London Press release: http://www.qmul.ac.uk/media/news/items/smd/44466.html
  13. ^ Press release in Chinese: http://www.ebiotrade.com/newsf/2011-2/2011216161538392.htm
  14. ^ Press release in The Times Online: http://www.timesonline.co.uk/tol/life_and_style/health/article6143744.ece
  15. ^ Press release in Medical Research Council (MRC) UK: http://www.timesonline.co.uk/tol/life_and_style/health/article6143744.ece
  16. ^ Press release in National Health Service (NHS): http://www.nhs.uk/news/2009/04April/Pages/NicotineGumCancer.aspx
  17. ^ Press release in Fox News: http://www.foxnews.com/story/0,2933,517415,00.html
  18. ^ Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 15 August 2002, 62 (16): 4773–80. PMID 12183437. 
  19. ^ Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 2004-04, 18 (7): 830–50. doi:10.1101/gad.1200704. PMC 387422. PMID 15082532. 
  20. ^ Wonsey DR, Follettie MT. Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res. 2005-06, 65 (12): 5181–9. doi:10.1158/0008-5472.CAN-04-4059. PMID 15958562. 
  21. ^ Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV. The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res. 2006-02, 66 (4): 2153–61. doi:10.1158/0008-5472.CAN-05-3003. PMID 16489016. 
  22. ^ Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH. Increased Levels of the FoxM1 Transcription Factor Accelerate Development and Progression of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice. Cancer Res. 2006-02, 66 (3): 1712–20. doi:10.1158/0008-5472.CAN-05-3138. PMC 1363687. PMID 16452231. 
  23. ^ Chan D, Yu S, Chiu P, Yao K, Liu V, Cheung A, Ngan H. Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis. J. Pathol. 2008-07, 215 (3): 245–52. doi:10.1002/path.2355. PMID 18464245. 
  24. ^ Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S. Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery. 2006-05, 139 (5): 665–70. doi:10.1016/j.surg.2005.10.012. PMID 16701100. 
  25. ^ Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH. Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Cancer Res. 2007-09, 67 (17): 8293–300. doi:10.1158/0008-5472.CAN-07-1265. PMID 17804744. 
  26. ^ Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res. 2006-04, 66 (7): 3593–602. doi:10.1158/0008-5472.CAN-05-2912. PMID 16585184. 
  27. ^ 27.0 27.1 Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT. Induction of Human Epithelial Stem/Progenitor Expansion by FOXM1. Cancer Res. 2010, 70 (22): 9515–9526. doi:10.1158/0008-5472.CAN-10-2173. PMC 3044465. PMID 21062979. 
  28. ^ Press release in the Independent: http://www.independent.co.uk/life-style/health-and-families/rogue-gene-invades-stem-cells-to-spark-cancer-study-2131802.html
  29. ^ Press release in the San Francisco Chronicle: http://www.sfgate.com/cgi-bin/article.cgi?f=/g/a/2010/11/09/prwebprweb4752264.DTL
  30. ^ Press release in the Sydney Morning Herald: http://news.smh.com.au/breaking-news-world/rogue-gene-invades-stem-cells-to-spark-cancer-study-20101110-17mc3.html
  31. ^ press release in Chinese: http://www.ebiotrade.com/newsf/2011-2/2011216161538392.htm
  32. ^ Teh et al., 2012, 国际癌症杂志 (Teh et al., Int. J Cancer, In press) http://onlinelibrary.wiley.com/doi/10.1002/ijc.27886/abstract
  33. ^ Press release in the Independent: http://www.independent.co.uk/life-style/health-and-families/rogue-gene-invades-stem-cells-to-spark-cancer-study-2131802.html
  34. ^ Press release in the San Francisco Chronicle: http://www.sfgate.com/cgi-bin/article.cgi?f=/g/a/2010/11/09/prwebprweb4752264.DTL
  35. ^ Press release in the Sydney Morning Herald: http://news.smh.com.au/breaking-news-world/rogue-gene-invades-stem-cells-to-spark-cancer-study-20101110-17mc3.html
  36. ^ press release in Chinese: http://www.ebiotrade.com/newsf/2011-2/2011216161538392.htm
  37. ^ Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat. Rev. Cancer. 2007-11, 7 (11): 847–59. doi:10.1038/nrc2223. PMID 17943136. 
  38. ^ Patent: http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012013931&recNum=1&maxRec=474&office=+%2528OF%253Awo%2529&prevFilter=&sortOption=Pub+Date+Desc&queryString=ALL%253A%2528queen+mary%2529&tab=PCT+Biblio
  39. ^ Teh et al., 2012, 国际癌症杂志 (Teh et al., Int. J Cancer, In press) http://onlinelibrary.wiley.com/doi/10.1002/ijc.27886/abstract