科學(xué)家們至少發(fā)現(xiàn)一個(gè)事例,，即當(dāng)較短的蛋白版本Chk1-S在細(xì)胞分裂開始發(fā)揮作用時(shí)，細(xì)胞分裂能夠繼續(xù)進(jìn)行,，癌癥病人可能有朝一日從這一發(fā)現(xiàn)中獲益,。
人們長期以來就知道蛋白Chk1是細(xì)胞發(fā)育中的一個(gè)關(guān)卡(checkpoint)：它阻止正常細(xì)胞和受損細(xì)胞發(fā)生分裂直到它們的DNA完全復(fù)制或修復(fù)。如今,，美國佐治亞衛(wèi)生科學(xué)大學(xué)和加州理工學(xué)院科學(xué)家們發(fā)現(xiàn)一種更短形式的他們稱之為Chk1-S(“S”代表短的意思)的蛋白能夠從根本上中和它的較長兄弟蛋白(longer sibling protein,，譯者注：即前面的Chk1)，這樣細(xì)胞分裂能夠繼續(xù)下去,。
這種較短形式的蛋白在癌細(xì)胞和胎兒組織中比較高水平地表達(dá),，因?yàn)檫@兩者需要加快細(xì)胞分裂。但是科學(xué)家們也證實(shí)在其他細(xì)胞中非常高水平的Chk1-S實(shí)際上減少腫瘤生長和提前促進(jìn)細(xì)胞分裂和死亡,。
加州理工學(xué)院博士后Navjotsingh Pabla說,，“Chk1對(duì)于所有細(xì)胞甚至是癌細(xì)胞的分裂而言是必須的，因而如果通過過量表達(dá)Chk1-S完全抑制它,，這些細(xì)胞也不能生長,。”在正常的非分裂細(xì)胞中，Chk1-S表達(dá)量接近于零,。
這些發(fā)現(xiàn)發(fā)表在《PNAS》期刊上,，表明這種短形式的蛋白有潛力輔助診斷和/或治療癌癥。Chk1抑制物在DNA復(fù)制/修復(fù)完全完成之前促進(jìn)異常細(xì)胞分裂---可能細(xì)胞死亡---發(fā)生,，已經(jīng)正在病人當(dāng)中進(jìn)行測試,。
佐治亞衛(wèi)生科學(xué)大學(xué)及查理-諾伍德退役老兵體檢中心(Charlie Norwood Veterans Affairs Medical Center)細(xì)胞生物學(xué)家Zheng Dong博士說，“Chk1-S只在DNA復(fù)制或修復(fù)時(shí)才表達(dá),，所以它結(jié)合到它的兄弟蛋白Chk1上并中和它，這樣細(xì)胞能夠分裂,。長期盤恒的一個(gè)問題是：如何調(diào)節(jié)Chk1,？”
他們發(fā)現(xiàn)無論DNA復(fù)制或修復(fù)是否完成，顯著增加的Chk1-S水平誘導(dǎo)細(xì)胞分裂,。不充分的DNA復(fù)制或修復(fù)不僅能夠?qū)е伦园l(fā)性細(xì)胞自殺,，而且還有能夠?qū)е掳┘?xì)胞產(chǎn)生的染色體或基因缺陷。此外,，癌細(xì)胞有目的發(fā)生突變抵抗治療,。Pabla猜想更短版本的蛋白表達(dá)可能在癌細(xì)胞中發(fā)生偏差，“我們非常有興趣去探究其中的奧秘”,。
Dong說,，“一種如此重要的蛋白以致于我們認(rèn)為它可能導(dǎo)致癌癥產(chǎn)生和有助于癌癥治療。我們有興趣發(fā)現(xiàn)該蛋白的重要調(diào)節(jié)物,。”
Chk1和Chk1-S是同一個(gè)基因發(fā)生不同剪接而產(chǎn)生的,。Chk1開啟表達(dá)的一種方法就是磷酸化,，而磷酸化能夠激活或去激活一種蛋白。當(dāng)需要DNA修復(fù)時(shí),，Chk1磷酸化水平特別有戲劇性,。Chk1接著通過磷酸化另一種蛋白而發(fā)揮作用，暫時(shí)中止細(xì)胞周期,。有意思的是,，當(dāng)Chk1磷酸化時(shí)，Chk1-S不能結(jié)合到它的兄弟蛋白,。眾所周知,，智力遲鈍能夠由一種磷酸化Chk1的DNA損傷檢測蛋白ATR發(fā)生突變造成。
盡管發(fā)育期間最大量細(xì)胞分裂發(fā)生,，在諸如血液,、皮膚和胃腸道之類的細(xì)胞周轉(zhuǎn)速度較高的地方，細(xì)胞分裂一生當(dāng)中都持續(xù)發(fā)生,。Dong說,，“大量組織需要再生。”(生物谷：towersimper編譯)
doi:10.1073/pnas.1104767109
PMC:
PMID:
Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints
Navjotsingh Pabla, Kirti Bhatt, and Zheng Dong
Checkpoint kinase 1 (Chk1) is a key regulator of checkpoint signaling in both the unperturbed cell cycle and DNA damage response. Under these conditions, Chk1 becomes active to prevent premature CDK1 activation and mitotic entry until DNA is properly replicated or repaired. It is unclear how Chk1 activity is controlled in the unperturbed cell cycle. During DNA damage, Chk1 is activated by ataxia telangiectasia and Rad3 related (ATR)-mediated phosphorylation; however, it is not entirely clear how this phosphorylation results in Chk1 activation. Here we report an N-terminally truncated alternative splice variant of Chk1, Chk1-S. Importantly, we show that Chk1-S is an endogenous repressor and regulator of Chk1. In the unperturbed cell cycle, Chk1-S interacts with and antagonizes Chk1 to promote the S-to-G2/M phase transition. During DNA damage, Chk1 is phosphorylated, which disrupts the Chk1–Chk1-S interaction, resulting in free, active Chk1 to arrest the cell cycle and facilitate DNA repair. Higher levels of Chk1-S are expressed, along with Chk1, in fetal and cancer tissues than in normal tissues. However, forced overexpression of Chk1-S in cultured cells and tumor xenografts induces premature mitotic entry, mitotic catastrophe, and reduction of tumor growth. The identification of Chk1-S as a unique splice variant and key regulator of Chk1 provides insights into cell cycle regulation and DNA damage response.
