生物谷報道：美國禮來公司（Eli Lilly and Company）和翻譯基因組學研究院（the Translational Genomics Research institute）研究人員日前宣布,，他們在乳腺癌,、結腸癌和卵巢癌中發(fā)現一種AKT1基因復發(fā)突變（recurring mutation，生物谷編者譯）,，這種突變AKT1基因誘導腫瘤細胞增殖,，并幫助癌細胞抵抗某些治療劑。相關文章刊登于Nature雜志,。
PI3-激酶/AKT途徑是人類腫瘤中最為活躍的細胞途徑之一,，導致癌細胞的生存和增長，途徑中的許多成分是新藥研發(fā)的候選靶標,。AKT1是該途徑的活性中心,，在癌癥中是聯系上游突變調控蛋白和下游存活信號途徑蛋白的中間環(huán)節(jié)。此次研究人員首次在在癌癥患者的臨床樣本中發(fā)現AKT1直接突變,，還未經細胞檢測,。
這項發(fā)現可以說是癌癥生物學中具有啟示意義的一個發(fā)現，證實AKT1是乳腺癌,、結腸癌和卵巢癌的致癌基因,。禮來公司Kerry L. Blanchard博士說，突變改變了PH（Pleckstrin同源序列,，酶與細胞膜上的磷脂結合的部分）區(qū)中結合袋（binding pocket）的靜電學特征,。研究人員分析了包括乳腺癌、結腸癌和卵巢癌在內的共150個腫瘤樣本,。數據分析結果顯示,，8％的乳腺癌、6％的結腸癌和2％的卵巢癌的樣本中,，AKT1發(fā)生突變,。
這是一個引人注目的研究，利用一系列久經考驗的技術發(fā)現腫瘤基因組加工過程的新問題,。James E. Thomas博士解釋說,，AKT1是一種蛋白激酶，在細胞生存,、增殖和代謝活動中發(fā)揮重要作用,。有趣的是，其它調控這些網絡的蛋白在肺癌,、前列腺癌,、結腸癌和腦癌中也有突變現象。AKT1中的這種突變明顯證實AKT1與癌癥形成有關,。
鑒定AKT1突變是禮來公司和TGen共同努力的結果,。這項發(fā)現證實,，臨床水平（非依賴于模型系統(tǒng)）研究癌癥遺傳學的重要性。
原始出處:
Nature advance online publication 4 July 2007 | doi:10.1038/nature05933; Received 8 March 2007; Accepted 11 May 2007; Published online 4 July 2007
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
John D. Carpten1, Andrew L. Faber2, Candice Horn2, Gregory P. Donoho2, Stephen L. Briggs3, Christiane M. Robbins1, Galen Hostetter1, Sophie Boguslawski2, Tracy Y. Moses1, Stephanie Savage1, Mark Uhlik2, Aimin Lin4, Jian Du2, Yue-Wei Qian4, Douglas J. Zeckner2, Greg Tucker-Kellogg5, Jeffrey Touchman1, Ketan Patel5, Spyro Mousses6, Michael Bittner1, Richard Schevitz3, Mei-Huei T. Lai2, Kerry L. Blanchard2 & James E. Thomas2
Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA
Cancer Discovery Research,
Global Structural Biology,
Integrative Biology, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA
Lilly Singapore Centre for Drug Discovery, 1 Science Park Road 04-01, The Capricorn, Singapore Science Park II, 117528 Singapore
Pharmaceutical Genomics, Translational Genomics Research Institute, TGen Suite 110, 13208 E. Shea Boulevard, Scottsdale, Arizona 85259, USA
Correspondence to: Kerry L. Blanchard2James E. Thomas2 Correspondence and requests for materials should be addressed to K.L.B. (Email: [email protected]) or J.E.T. (Email: [email protected]).
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
