Staveley B E, Ruel L, Jin J, Stambolic V, Mastronardi F G, Heitzler P, Woodgett J R, Manoukian A S
Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Canada.
Curr Biol. 1998 May 7;8(10):599-602. doi: 10.1016/s0960-9822(98)70231-3.
The decision between survival and death is an important aspect of cellular regulation during development and malignancy. Central to this regulation is the process of apoptosis, which is conserved in multicellular organisms [1]. A variety of signalling cascades have been implicated in modulation of apoptosis, including the phosphatidylinositol (Pl) 3-kinase pathway. Activation of Pl 3-kinase is protective, and inhibition of this lipid kinase enhances cell death under several conditions including deregulated expression of c-Myc, neurotrophin withdrawal and anoikis [2-7]. Recently, the protective effects of Pl 3-kinase have been linked to its activation of the pleckstrin homology (PH)-domain-containing protein kinase B (PKB or AKT) [8]. PKB/AKT was identified from an oncogene, v-akt, found in a rodent T-cell lymphoma [9]. To initiate a genetic analysis of PKB, we have isolated and characterized a Drosophila PKB/AKT mutant (termed Dakt1) that exhibits ectopic apoptosis during embryogenesis as judged by induction of membrane blebbing, DNA fragmentation and macrophage infiltration. Apoptosis caused by loss of Dakt function is rescued by caspase suppression but is distinct from the previously described reaper/grim/hid functions. These data implicate Dakt1 as a cell survival gene in Drosophila, consistent with cell protection studies in mammals.
生死抉择是发育和恶性肿瘤过程中细胞调控的一个重要方面。这种调控的核心是细胞凋亡过程，该过程在多细胞生物中是保守的[1]。多种信号级联反应与细胞凋亡的调节有关，包括磷脂酰肌醇（Pl）3-激酶途径。Pl 3-激酶的激活具有保护作用，在包括c-Myc表达失调、神经营养因子撤离和失巢凋亡等多种情况下，抑制这种脂质激酶会增强细胞死亡[2-7]。最近，Pl 3-激酶的保护作用与其对含普列克底物蛋白同源（PH）结构域的蛋白激酶B（PKB或AKT）的激活有关[8]。PKB/AKT是从一种在啮齿动物T细胞淋巴瘤中发现的癌基因v-akt中鉴定出来的[9]。为了对PKB进行遗传学分析，我们分离并鉴定了一种果蝇PKB/AKT突变体（称为Dakt1），通过膜泡形成、DNA片段化和巨噬细胞浸润的诱导判断，该突变体在胚胎发育过程中表现出异位凋亡。Dakt功能丧失引起的细胞凋亡可通过抑制半胱天冬酶得到挽救，但与先前描述的收割者/严峻/隐藏功能不同。这些数据表明Dakt1是果蝇中的一个细胞存活基因，这与哺乳动物中的细胞保护研究一致。
