生物谷：干細(xì)胞是全能型的,，可以分化成任何一種細(xì)胞,，而干細(xì)胞中的Oct4蛋白質(zhì)起著調(diào)控作用，決定干細(xì)胞是繼續(xù)分化成其他特殊細(xì)胞,，還是保持干細(xì)胞的多功能性,。通過化學(xué)途徑可以改變Oct4蛋白質(zhì)，從而決定干細(xì)胞的命運(yùn),。德國馬普分子生物醫(yī)學(xué)所所長漢斯·施勒和美國賓西法尼亞大學(xué)研究人員共同發(fā)現(xiàn)了一個(gè)Oct4蛋白新的調(diào)控機(jī)制,，一種特殊的蛋白質(zhì)可以和干細(xì)胞標(biāo)記結(jié)合,，從而延長蛋白質(zhì)的生命和增強(qiáng)讀取基因信息的功能。這項(xiàng)新發(fā)現(xiàn)被刊登在最新一期的《生物化學(xué)雜志》上,。
施勒介紹說,，干細(xì)胞的多功能程度是有限的，它既可以發(fā)展成不同組織的細(xì)胞,，也可以發(fā)展成腫瘤細(xì)胞,，其發(fā)展方向在很大程度上受Oct4蛋白質(zhì)影響。施勒和美國賓西法尼亞大學(xué)的同事在合作研究中發(fā)現(xiàn),，Oct4能與基因中的轉(zhuǎn)錄因子結(jié)合,，通過這種方式使干細(xì)胞保持其多能性，并使干細(xì)胞僅向一個(gè)方向發(fā)展,?？茖W(xué)家認(rèn)為，Oct4可以有不同的作用機(jī)制,，在和轉(zhuǎn)錄因子結(jié)合期間,，一些小分子的結(jié)合會(huì)導(dǎo)致蛋白質(zhì)的化學(xué)變化。研究表明,，所謂的SUMO蛋白質(zhì)和轉(zhuǎn)錄因子有很強(qiáng)的結(jié)合傾向,，并以此改變其功能。
他們的實(shí)驗(yàn)顯示,，SUMO－1（4種SUMO蛋白的一種）可以結(jié)合到Oct4蛋白上,，從而延長了Oct4的生命。他們把SUMO1和Oct4蛋白注入活性干細(xì)胞中,，用顯微鏡觀察熒光抗體來檢測,，發(fā)現(xiàn)這兩種蛋白質(zhì)分子互相結(jié)合在一起。研究人員又分析了SUMO－1蛋白質(zhì)結(jié)合點(diǎn)的位置,，有目的地使Oct4可能的結(jié)合點(diǎn)失效,，人為地使118號(hào)賴氨酸作為結(jié)合點(diǎn)。由于這個(gè)點(diǎn)在DNA結(jié)合點(diǎn)附近,，結(jié)果發(fā)現(xiàn),，SUMO－1和Oct4的結(jié)合體能更加有效地結(jié)合到DNA上。
研究人員還發(fā)現(xiàn),，Oct4和SUMO－1蛋白質(zhì)的結(jié)合體可以更好地操縱轉(zhuǎn)錄啟動(dòng)因子,，SUMO－1不僅改善Oct4蛋白質(zhì)功能，并且延長Oct4的壽命,。在兩種蛋白質(zhì)注入活細(xì)胞16小時(shí)后,，結(jié)合蛋白質(zhì)形態(tài)比未結(jié)合形態(tài)多4倍。換言之，通過結(jié)合到Oct4上,，SUMO－1調(diào)控干細(xì)胞內(nèi)Oct4的含量,，并由此決定干細(xì)胞是向正常方向還是向腫瘤方向分化，這個(gè)發(fā)現(xiàn)很可能對腫瘤治療有所幫助,，特別是對于高Oct4蛋白質(zhì)濃度造成的腫瘤,。（科技日報(bào)）
原始出處:
J. Biol. Chem., Vol. 282, Issue 29, 21551-21560, July 20, 2007
Sumoylation of Oct4 Enhances Its Stability, DNA Binding, and Transactivation*
Fang Wei, Hans R. Schöler, and Michael L. Atchison1
From the Department of Animal Biology, Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and Max Planck Institute of Molecular Biomedicine, Röntgenstrasse 20, D-48149 Münster, Germany
Transcription factor Oct4 is a master regulator affecting the fate of pluripotent stem cells and germ cell precursors. Oct4 expression is tightly regulated, and small changes in expression level can have dramatic effects on differentiation or oncogenesis. Post-translational modifications including phosphorylation and ubiquitination have been reported to regulate Oct4 transcriptional activity. Here we show that Oct4 is a target for small ubiquitin-related modifier (SUMO)-1 modification in vivo and in vitro. Sumoylation of Oct4 occurs at a single lysine, Lys118, located at the end of the amino-terminal transactivation domain and next to the Pit1-Oct-Unc86 (POU) DNA binding domain. SUMO-1 and Oct4 colocalize at several promoter sequences in vivo, and a fraction of Oct4 molecules colocalized with SUMO-1 in nuclear aggregates. Sumoylation of Oct4 led to significantly increased Oct4 stability and increased DNA binding. In addition, SUMO-1 cotransfection led to augmented Oct4 transactivation potential that was reduced when the Oct4 sumoylation target site was mutated. Therefore, sumoylation of Oct4 results in increased stability, DNA binding, and transactivation and provides an important mechanism to regulate Oct4 activity.
