Class I A phosphoinositide 3-kinases (PI3Ks) are activated by growth factor receptors, and they regulate, among other processes, cell growth and organ size. Studies using transgenic mice overexpressing constitutively active and dominant negative forms of the p110␣ catalytic subunit of class I A PI3K have implicated the role of this enzyme in regulating heart size and physiological cardiac hypertrophy. To further understand the role of class I A PI3K in controlling heart growth and to circumvent potential complications from the overexpression of dominant negative and constitutively active proteins, we generated mice with muscle-specific deletion of the p85␣ regulatory subunit and germ line deletion of the p85 regulatory subunit of class I A PI3K. Here we show that mice with cardiac deletion of both p85 subunits exhibit attenuated Akt signaling in the heart, reduced heart size, and altered cardiac gene expression. Furthermore, exercise-induced cardiac hypertrophy is also attenuated in the p85 knockout hearts. Despite such defects in postnatal developmental growth and physiological hypertrophy, the p85 knockout hearts exhibit normal contractility and myocardial histology. Our results therefore provide strong genetic evidence that class I A PI3Ks are critical regulators for the developmental growth and physiological hypertrophy of the heart.
The evolutionarily conserved phosphoinositide 3-kinase (PI3K) signaling pathway mediates both the metabolic effects of insulin and the growth-promoting effects of insulin-like growth factor-1 (IGF-1). We have generated mice deficient in both the p85alpha/p55alpha/p50alpha and the p85beta regulatory subunits of class I(A) PI3K in skeletal muscles. PI3K signaling in the muscle of these animals is severely impaired, leading to a significant reduction in muscle weight and fiber size. These mice also exhibit muscle insulin resistance and whole-body glucose intolerance. Despite their ability to maintain normal fasting and fed blood glucose levels, these mice show increased body fat content and elevated serum free fatty acid and triglyceride levels. These results demonstrate that in vivo p85 is a critical mediator of class I(A) PI3K signaling in the regulation of muscle growth and metabolism. Our finding also indicates that compromised muscle PI3K signaling could contribute to symptoms of hyperlipidemia associated with human type 2 diabetes.
Mice with heterozygous deletion of the PTEN tumor suppressor gene develop a range of epithelial neoplasia as well as lymphoid hyperplasia. Previous studies suggest that PTEN suppresses tumor formation by acting as a phosphoinositide phosphatase to limit signaling by phosphoinositide 3-kinase (PI3K). Here, we examined the effect of deleting various regulatory subunits of PI3K (p85␣ and p85) on epithelial neoplasia and lymphoid hyperplasia in PTEN ؉/؊ mice. Interestingly, we found the loss of one p85␣ allele with or without the loss of p85 led to increased incidence of intestinal polyps. Signaling downstream of PI3K was enhanced in the PTEN ؉/؊ p85␣ ؉/؊ p85 ؊/؊ polyps, as judged by an increased fraction of both cells with cytoplasmic staining of the transcription factor FKHR and cells with positive staining for the proliferation marker Ki-67. In contrast, the incidence of prostate intraepithelial neoplasia was not significantly altered in PTEN ؉/؊ mice heterozygous for p85␣ or null for p85, whereas the fraction of proliferating cells in prostate intraepithelial neoplasia was reduced in mice lacking p85. Finally, there was no significant change in T lymphocyte hyperplasia in the PTEN ؉/؊ mice with various p85 deletions, although anti-CD3-stimulated AKT activation was somewhat reduced in the p85␣ ؉/؊ background. These results indicate that decreasing the levels of different p85 regulatory subunits can result in enhanced PI3K signaling in some tissues and decreased PI3K signaling in others, supporting the model that, although p85 proteins are essential for class I A PI3K signaling, they can function as inhibitors of PI3K signaling in some tissues and thus suppress tumor formation.intestinal polyps ͉ prostate intraepithelial neoplasia ͉ AKT P hosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that regulate a wide range of cellular processes, among which are cell survival, growth, and proliferation, processes whose misregulation contributes to cancer (1, 2). Class I PI3Ks phosphorylates the 3Ј-hydroxyl group on the inositol ring of the lipid phosphatidylinositol-4,5-bisphosphate to generate the membrane-bound second messenger phosphatidylinositiol-3,4,5-trisphosphate (PIP 3 ), which in turn activates a number of downstream proteins through interaction with their pleckstrinhomology domains.A major downstream target of PIP 3 is the protein serinethreonine kinase Akt (also known as PKB). PIP 3 recruits Akt to the plasma membrane through binding to its pleckstrinhomology domain. At the plasma membrane, the protein kinase PDK1 phosphorylates Thr-308 in the catalytic loop of Akt and hence activates it (1). Full activation of Akt requires additional phosphorylation at Ser-473 in its C terminus (3). Akt regulates the activity of a number of cellular proteins and mediates many of the downstream effects of PI3K. The FOXO (forkhead) family of transcription factors act as negative regulators of cell survival and cell cycle progression through their transcriptional activation of proapoptotic proteins such as FAS-l...
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