Characterization of the molecular mechanisms of Akt activation

丝氨酸苏氨酸激酶Akt，也称为PKB（蛋白激酶B），在细胞内存活的调节中起核心作用。这种Akt信号通路的失调是各种人类肿瘤疾病的基础。最近，原癌基因TCL 1（T细胞白血病1），具有以前未知的生理功能，显示与Akt pleckstrin同源结构域相互作用，增强Akt激酶活性;因此，它作为Akt激酶共激活剂发挥作用。与TCL 1基因在各种人类肿瘤疾病中高度活化的病理条件相反，TCL 1的生理表达严格限于早期发育细胞以及免疫细胞的各种发育阶段。近端TCL 1启动子序列的NBRE（Nerve Growth Factor Responsive Element，神经生长因子应答元件）以负反馈机制调节TCL 1的限制性生理表达。此外，基于Akt-TCL 1蛋白复合物的NMR结构研究，已经鉴定了由TCL 1的βA链组成的抑制肽“Akt-in”，并且其具有治疗潜力。我们的研究共同促进了对TCL 1-Akt功能相互作用和原癌基因TCL 1家族的生物学作用以及对Akt（核心细胞内存活调节因子）特异性的新抑制性药物的实质性理解。

Serine threonine kinase Akt, also called PKB (Protein Kinase B), plays a central role in the regulation of intracellular survival. Deregulation of this Akt signaling pathway underlies various human neoplastic diseases. Recently, the protooncogene TCL1 (T cell leukemia 1), with a previously unknown physiological function, was shown to interact with the Akt pleckstrin homology domain, enhancing Akt kinase activity; hence, it functions as an Akt kinase co-activator. In contrast to pathological conditions in which the TCL1 gene is highly activated in various human neoplasmic diseases, the physiological expression of TCL1 is tightly limited to early developmental cells as well as various developmental stages of immune cells. The NBRE (Nerve Growth Factor Responsive Element) of the proximal TCL1 promoter sequences can regulate the restricted physiological expression of TCL1 in a negative feedback mechanism. Further, based on the NMR structural studies of Akt-TCL1 protein complexes, an inhibitory peptide, "Akt-in," consisting of the βA strand of TCL1, has been identified and has therapeutic potential. Our study together promote substantial understanding of TCL1-Akt functional interaction and the biological action of the protooncogene TCL1 family and the new suppressive drug specific for Akt, a core intracellular survival regulator.