Shioi Tetsuo, McMullen Julie R, Kang Peter M, Douglas Pamela S, Obata Toshiyuki, Franke Thomas F, Cantley Lewis C, Izumo Seigo
Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Mol Cell Biol. 2002 Apr;22(8):2799-809. doi: 10.1128/MCB.22.8.2799-2809.2002.
One of the least-understood areas in biology is the determination of the size of animals and their organs. In Drosophila, components of the insulin receptor phosphoinositide 3-kinase (PI3K) pathway determine body, organ, and cell size. Several biochemical studies have suggested that Akt/protein kinase B is one of the important downstream targets of PI3K. To examine the role of Akt in the regulation of organ size in mammals, we have generated and characterized transgenic mice expressing constitutively active Akt (caAkt) or kinase-deficient Akt (kdAkt) specifically in the heart. The heart weight of caAkt transgenic mice was increased 2.0-fold compared with that of nontransgenic mice. The increase in heart size was associated with a comparable increase in myocyte cell size in caAkt mice. The kdAkt mutant protein attenuated the constitutively active PI3K-induced overgrowth of the heart, and the caAkt mutant protein circumvented cardiac growth retardation induced by a kinase-deficient PI3K mutant protein. Rapamycin attenuated caAkt-induced overgrowth of the heart, suggesting that the mammalian target of rapamycin (mTOR) or effectors of mTOR mediated caAkt-induced heart growth. In conclusion, Akt is sufficient to induce a marked increase in heart size and is likely to be one of the effectors of the PI3K pathway in mediating heart growth.
生物学中最不为人所理解的领域之一是动物及其器官大小的决定机制。在果蝇中，胰岛素受体磷酸肌醇3激酶（PI3K）信号通路的组成部分决定了身体、器官和细胞的大小。多项生化研究表明，Akt/蛋白激酶B是PI3K重要的下游靶点之一。为了研究Akt在哺乳动物器官大小调节中的作用，我们构建并鉴定了在心脏中特异性表达组成型活性Akt（caAkt）或激酶缺陷型Akt（kdAkt）的转基因小鼠。与非转基因小鼠相比，caAkt转基因小鼠的心脏重量增加了2.0倍。caAkt小鼠心脏大小的增加与心肌细胞大小的相应增加有关。kdAkt突变蛋白减弱了组成型活性PI3K诱导的心脏过度生长，而caAkt突变蛋白则克服了激酶缺陷型PI3K突变蛋白诱导的心脏生长迟缓。雷帕霉素减弱了caAkt诱导的心脏过度生长，这表明雷帕霉素的哺乳动物靶点（mTOR）或mTOR的效应器介导了caAkt诱导的心脏生长。总之，Akt足以诱导心脏大小显著增加，并且可能是PI3K信号通路介导心脏生长的效应器之一。
