Ubiquitous expression of the Pik3ca(H1047R) mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly
Kathryn M Kinross, Karen G Montgomery, Salvatore P Mangiafico, Lauren M Hare, Margarete Kleinschmidt, Megan J Bywater, Ingrid J Poulton, Christina Vrahnas, Holger Henneicke, Jordane Malaterre, Paul M Waring, Carleen Cullinane, Natalie A Sims, Grant A McArthur, Sofianos Andrikopoulos, Wayne A Phillips
FASEB JOURNAL | FEDERATION AMER SOC EXP BIOL | Published : 2015
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..View full abstract
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Awarded by National Health and Medical Research Council of Australia
The authors thank Ryan Galea, Kevin Mills, Kerry Ardley, the animal facility staff, the Peter MacCallum Cancer Centre Department of Pathology, and the Research Division Microscopy and Histology Core Facility for their valuable advice and/or technical assistance. This work was supported, in part, by the National Health and Medical Research Council of Australia (project Grants 628620 and 628621, to W.A.P.). K.K. was supported by a grant-in-aid from the Cancer Council of Victoria.