Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12551
Title: Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly.
Authors: 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
Affiliation: 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
St. Vincent's Institute of Medical Research and University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia
University of Melbourne Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
*Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
and University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia wayne.phillips@petermac.org.
Translational Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Issue Date: 30-Dec-2014
Citation: Faseb Journal : Official Publication of the Federation of American Societies For Experimental Biology 2014; 29(4): 1426-34
Abstract: 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.-Kinross, K. M., Montgomery, K. G., Mangiafico, S. P., Hare, L. M., Kleinschmidt, M., Bywater, M. J., Poulton, I. J., Vrahnas, C., Henneicke, H., Malaterre, J., Waring, P. M., Cullinane, C., Sims, N. A., McArthur, G. A., Andrikopoulos, S., Phillips, W. A. Ubiquitous expression of the Pik3ca(H1047R) mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly.
Internal ID Number: 25550458
URI: http://ahro.austin.org.au/austinjspui/handle/1/12551
DOI: 10.1096/fj.14-262782
URL: http://www.ncbi.nlm.nih.gov/pubmed/25550458
Type: Journal Article
Subjects: PI3K
glucose metabolism
mouse model
overgrowth syndrome
p110α
Appears in Collections:Journal articles

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