Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner.
Activation of the serine/threonine kinase Akt/PKB positively impacts on three cellular processes relevant to tumor progression: proliferation, survival, and cell size/growth. Using a three-dimensional culture model of MCF-10A mammary cells, we have examined how Akt influences the morphogenesis of polarized epithelial structures. Activation of a conditionally active variant of Akt elicits large, misshapen structures, which primarily arise from the combined effects of Akt on proliferation and cell size. Importantly, Akt activation amplifies proliferation during the early stages of morphogenesis, but cannot overcome signals suppressing proliferation in late-stage cultures. Akt also cooperates with oncoproteins such as cyclin D1 or HPV E7 to promote proliferation and morphogenesis in the absence of growth factors. Pharmacological inhibition of the Akt effector, mammalian target of rapamycin (mTOR), with rapamycin prevents the morphological disruption elicited by Akt activation, including its effect on cell size and number, and the cooperative effect of Akt on oncogene-driven proliferation, indicating that mTOR function is required for the multiple biological effects of Akt activation during morphogenesis.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Jayanta
J
Debnath
Stephanie J
SJ
Walker
Joan S
JS
Brugge
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001940:Breast / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D016764:Cell Polarity / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009024:Morphogenesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt; D012190:Retroviridae / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D004247:DNA; D011494:Protein Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus