Mammalian target of rapamycin is the key effector of phosphatidylinositol-3-OH-initiated proliferative signals in the thyroid follicular epithelium.
Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasingly recognized as a common feature of thyroid follicular neoplasms. We have recently shown that conditional loss of Pten in the mouse thyroid follicular cells is sufficient to stimulate continuous autonomous growth, leading to a homogeneously hyperplastic gland and to the development of follicular adenomas. Because the PI3K/AKT cascade can activate a plethora of different signaling pathways, it is still unclear which of these may represent the key mitogenic output of PI3K-initiated signaling. Here, we show that the in vivo proliferative response to chronic PI3K activation profoundly relies on the activation of the mammalian target of rapamycin (mTOR)/S6K1 axis, and that mTOR inhibition in Pten mutant mice and cells restores virtually normal proliferation rates, despite the presence of still elevated Akt activity, at least in part by down-regulating cyclins D1 and D3, and without affecting cell survival.
Yeager
Nicole
N
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Brewer
Charlene
C
Cai
Kathy Qi
KQ
Xu
Xiang-Xi
XX
Di Cristofano
Antonio
A
D018263:Adenocarcinoma, Follicular / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004848:Epithelium / Q000378:metabolism / Q000502:physiology*; D000068338:Everolimus; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013961:Thyroid Gland / Q000378:metabolism / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000473:pathology
D000068338:Everolimus; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C487757:Pten protein, mouse