Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kγ

Takehiko Sasaki, Junko Irie-Sasaki, Yasuo Horie, Kurt Bachmaier, Jimmie E. Fata, Martin Li, Akira Suzuki, Dennis Bouchard, Alexandra Ho, Mark Redston, Steven Gallinger, Rama Khokha, Tak W. Mak, Phillip T. Hawkins, Len Stephens, Stephen W. Scherer, Ming Tsao and Josef M. Penninger ()
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Takehiko Sasaki: University of Toronto
Junko Irie-Sasaki: University of Toronto
Kurt Bachmaier: University of Toronto
Jimmie E. Fata: Ontario Cancer Institute University of Toronto
Martin Li: The Hospital for Sick Children
Akira Suzuki: University of Toronto
Dennis Bouchard: University of Toronto
Alexandra Ho: University of Toronto
Mark Redston: Centre for Cancer Genetics, Samuel Lunenfeld Research Institute
Steven Gallinger: Centre for Cancer Genetics, Samuel Lunenfeld Research Institute
Rama Khokha: Ontario Cancer Institute University of Toronto
Tak W. Mak: University of Toronto
Phillip T. Hawkins: The Babraham Institute, Babraham
Len Stephens: The Babraham Institute, Babraham
Stephen W. Scherer: The Hospital for Sick Children
Ming Tsao: University of Toronto
Josef M. Penninger: University of Toronto

Nature, 2000, vol. 406, issue 6798, 897-902

Abstract: Abstract 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 apoptosis1,2. 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 tumorigenesis5,6,7. Thus, a model has arisen that PI(3)Ks promote development of cancers. Here we report that genetic inactivation of the p110γ catalytic subunit of PI(3)Kγ (ref. 8) leads to development of invasive colorectal adenocarcinomas in mice. In humans, p110γ protein expression is lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines. Overexpression of wild-type or kinase-dead p110γ in human colon cancer cells with mutations of the tumour suppressors APC and p53 , or the oncogenes β-catenin and Ki-ras, suppressed tumorigenesis. Thus, loss of p110γ in mice leads to spontaneous, malignant epithelial tumours in the colorectum and p110γ can block the growth of human colon cancer cells.

Date: 2000
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DOI: 10.1038/35022585

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