抑癌基因是一類抑制細(xì)胞過度生長,、增殖從而遏制腫瘤形成的基因,。對(duì)于正常細(xì)胞,，調(diào)控生長的基因（如原癌基因等）和調(diào)控抑制生長的基因（如抑癌基因等）的協(xié)調(diào)表達(dá)是調(diào)節(jié)控制細(xì)胞生長的重要分子機(jī)制之一。目前定論的抑癌基因有10余種,，p53基因就是其中較為出名的一個(gè),，由于p53蛋白在維持細(xì)胞正常生長,、抑制惡性增殖中起著重要作用，因而被冠以“基因衛(wèi)士”稱號(hào),。
來自哥倫比亞大學(xué)癌癥遺傳學(xué)研究所,，北京大學(xué)醫(yī)學(xué)部，貝勒醫(yī)學(xué)院的研究人員揭示了著名抑癌基因p53與ARF作用途徑的新機(jī)制,，并且發(fā)現(xiàn)了一種新型酶，闡明了這種酶在p53與ARF作用途徑中的作用,。這一研究成果公布在Nature雜志上,。
在腫瘤脅迫（oncogenic stress）下p53的激活需要一種腫瘤抑制因子：ARF，近期的研究顯示p53激活是通過ARF介導(dǎo)的,，但是并不是由DNA損傷誘發(fā)的,，而是針對(duì)體內(nèi)某種生理?xiàng)l件下產(chǎn)生腫瘤生長的主要保護(hù)方式，這說明ARF-p53具有比之前預(yù)想的更多的基礎(chǔ)功能,。
ARF也是一種在大多數(shù)人類細(xì)胞系中非常穩(wěn)定的細(xì)胞因子,，科學(xué)家們認(rèn)為ARF主要在轉(zhuǎn)錄水平上被誘導(dǎo)表達(dá)，并且ARF-p53途徑的激活要比p53被DNA損傷激活這一過程慢得多,，而且也是不可逆的,。
在這篇文章中，研究人員發(fā)現(xiàn)ARF在正常人類細(xì)胞中非常不穩(wěn)定,，但是在癌細(xì)胞中降解被抑制,。研究人員通過生物化學(xué)純化，分離出了ARF的一種特殊的泛素酶,，并將這種酶命名為ULF,，他們發(fā)現(xiàn)這種酶在體內(nèi)和體外都能與ARF作用，促進(jìn)ARF的降解,。ULF敲除實(shí)驗(yàn)也證明敲除ULF后,，正常細(xì)胞中ARF更加穩(wěn)定了。
進(jìn)一步的研究還發(fā)現(xiàn)NPM和c-Myc這兩種癌細(xì)胞中常見的過表達(dá)蛋白,，能抑制ULF介導(dǎo)的ARF泛素化過程,，從而促進(jìn)ARF在癌細(xì)胞中的穩(wěn)定性。這些研究數(shù)據(jù)揭示了ARF-p53途徑的動(dòng)力學(xué)特征,，也闡明了在應(yīng)答腫瘤脅迫過程中,，非轉(zhuǎn)錄依賴性機(jī)制對(duì)于ARF調(diào)控作用的重要性。
近期p53研究又獲得了許多成果,，比較引人注目的是來自Dartmouth醫(yī)學(xué)院的研究人員p53具有抑制非二倍體細(xì)胞進(jìn)行有絲分裂的作用,。只有當(dāng)p53失效或是缺失的時(shí)候，抑制異倍體有絲分裂的功效停止,，導(dǎo)致細(xì)胞無限制地復(fù)制下去,，這樣變成癌細(xì)胞樣細(xì)胞,。
2008年來自Dartmouth醫(yī)學(xué)院的Sarah Thompson和Duane Compton發(fā)現(xiàn)，大部分的染色體不穩(wěn)定狀態(tài)下的細(xì)胞與錯(cuò)誤的染色體著絲粒和有絲分裂紡錘體有關(guān)聯(lián),。正常的細(xì)胞在染色體異常分配下會(huì)停止有絲分裂,，而腫瘤細(xì)胞中的異倍體卻不會(huì)停止有絲分裂，這是什么原因,？
Sarah研究小組為了追蹤這一真相,，通過人工改造人類細(xì)胞，在染色體上加上熒光蛋白標(biāo)記,，這樣可以觀察有絲分裂中這些細(xì)胞染色體的分配過程,。
他們?nèi)藶榈卣T導(dǎo)細(xì)胞有絲分裂染色體異常分配，并通過熒光標(biāo)記來區(qū)分正常和異常的細(xì)胞,，結(jié)果發(fā)現(xiàn),，正常情況下異倍體的細(xì)胞停止分裂。在這些停止分裂的細(xì)胞中,，發(fā)現(xiàn)p53以及相關(guān)轉(zhuǎn)錄產(chǎn)物p21表達(dá)量異常高,。(生物谷Bioon.com)
生物谷推薦原文出處：
Nature doi:10.1038/nature08820
Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses
Delin Chen1, Jing Shan1, Wei-Guo Zhu2, Jun Qin3 & Wei Gu1
1Institute for Cancer Genetics, and Department of Pathology and Cell Biology College of Physicians & Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA
2Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
3Departments of Biochemistry and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress1, 2, 3, 4, 5, 6. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings7, 8, suggesting that the ARF–p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF–p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF–p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.
