Kinross Kathryn M, Montgomery Karen G, Mangiafico Salvatore P, Hare Lauren M, Kleinschmidt Margarete, Bywater Megan J, Poulton Ingrid J, Vrahnas Christina, Henneicke Holger, Malaterre Jordane, Waring Paul M, Cullinane Carleen, Sims Natalie A, McArthur Grant A, Andrikopoulos Sofianos, Phillips Wayne A
*Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
*Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia; Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia; Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; **Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia
FASEB J. 2015 Apr;29(4):1426-34. doi: 10.1096/fj.14-262782. Epub 2014 Dec 30.
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5%; wild-type 117 ± 3%, mean ± sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 ± 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion of Akt2 increased median survival by 44%, neither organ overgrowth, nor hypoglycemia were rescued, indicating that both the growth and metabolic functions of constitutive PI3K activity can be Akt2 independent. This mouse model demonstrates the critical role of PI3K in the regulation of both organ size and glucose metabolism at the whole animal level.
PIK3CA基因编码PI3K的p110α催化亚基，该基因的突变是人类癌症中最常见的突变之一，最近还与一系列人类过度生长综合征有关。我们采用了一种新型的诱导性“外显子开关”方法，将组成型活性Pik3ca(H1047R)突变敲入小鼠的内源性Pik3ca基因中。Pik3ca(H1047R)突变在全身的普遍表达导致诱导后3周内体重显著增加（突变体为150±5%；野生型为117±3%，平均值±标准误），这与器官大小增加而非肥胖有关。还观察到严重的代谢影响，包括诱导后11天血糖水平降至基线的59±4%以及胰岛素水平检测不到。Pik3ca(H1047R)突变小鼠比野生型对照小鼠更早死亡（突变诱导后中位生存期为46.5天）（野生型100%存活>250天）。虽然删除Akt2可使中位生存期延长44%，但器官过度生长和低血糖均未得到缓解，这表明组成型PI3K活性的生长和代谢功能都可以不依赖Akt2。该小鼠模型证明了PI3K在整个动物水平上对器官大小和葡萄糖代谢调节中的关键作用。
