Sasaki T, Irie-Sasaki J, Horie Y, Bachmaier K, Fata J E, Li M, Suzuki A, Bouchard D, Ho A, Redston M, Gallinger S, Khokha R, Mak T W, Hawkins P T, Stephens L, Scherer S W, Tsao M, Penninger J M
Ontario Cancer Institute, and Department of Medical Biophysics and Immunology, University of Toronto, Canada.
Nature. 2000 Aug 24;406(6798):897-902. doi: 10.1038/35022585.
Phosphoinositide-3-OH kinases (PI(3)Ks) constitute a family of evolutionarily conserved lipid kinases that regulate a vast array of fundamental cellular responses, including proliferation, transformation, differentiation and protection from apoptosis. PI(3)K-mediated activation of the cell survival kinase PKB/Akt, and negative regulation of PI(3)K signalling by the tumour suppressor PTEN (refs 3, 4) are key regulatory events in tumorigenesis. Thus, a model has arisen that PI(3)Ks promote development of cancers. Here we report that genetic inactivation of the p110gamma catalytic subunit of PI(3)Kgamma (ref. 8) leads to development of invasive colorectal adenocarcinomas in mice. In humans, p110gamma protein expression is lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines. Overexpression of wild-type or kinase-dead p110gamma in human colon cancer cells with mutations of the tumour suppressors APC and p53, or the oncogenes beta-catenin and Ki-ras, suppressed tumorigenesis. Thus, loss of p110gamma in mice leads to spontaneous, malignant epithelial tumours in the colorectum and p110gamma can block the growth of human colon cancer cells.
磷酸肌醇-3-羟基激酶（PI(3)Ks）构成了一个进化上保守的脂质激酶家族，可调节大量基本的细胞反应，包括增殖、转化、分化以及对细胞凋亡的保护。PI(3)K介导的细胞存活激酶PKB/Akt的激活，以及肿瘤抑制因子PTEN对PI(3)K信号的负调控（参考文献3、4）是肿瘤发生中的关键调控事件。因此，出现了一种PI(3)Ks促进癌症发展的模型。在此我们报告，PI(3)Kγ的p110γ催化亚基的基因失活（参考文献8）会导致小鼠侵袭性结直肠癌的发生。在人类中，原发性结直肠癌患者和结肠癌细胞系中p110γ蛋白表达缺失。在具有肿瘤抑制因子APC和p53或癌基因β-连环蛋白和Ki-ras突变的人类结肠癌细胞中，野生型或激酶失活的p110γ的过表达抑制了肿瘤发生。因此，小鼠中p110γ的缺失会导致结肠直肠自发性恶性上皮肿瘤，并且p110γ可阻断人类结肠癌细胞的生长。
