Debnath Jayanta, Walker Stephanie J, Brugge Joan S
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
J Cell Biol. 2003 Oct 27;163(2):315-26. doi: 10.1083/jcb.200304159. Epub 2003 Oct 20.
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.
丝氨酸/苏氨酸激酶Akt/PKB的激活对与肿瘤进展相关的三个细胞过程产生积极影响：增殖、存活以及细胞大小/生长。利用MCF-10A乳腺细胞的三维培养模型，我们研究了Akt如何影响极化上皮结构的形态发生。激活Akt的条件性活性变体可引发大的、畸形的结构，这主要源于Akt对增殖和细胞大小的综合影响。重要的是，Akt激活在形态发生的早期阶段会放大增殖，但无法克服晚期培养中抑制增殖的信号。Akt还与细胞周期蛋白D1或人乳头瘤病毒E7等癌蛋白协同作用，在缺乏生长因子的情况下促进增殖和形态发生。用雷帕霉素对Akt效应器——雷帕霉素哺乳动物靶蛋白（mTOR）进行药理学抑制，可防止由Akt激活引发的形态破坏，包括其对细胞大小和数量的影响，以及Akt对癌基因驱动增殖的协同作用，这表明mTOR功能是Akt激活在形态发生过程中产生多种生物学效应所必需的。
