Proteasomal degradation of the Fox01 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins
Proteasomal degradation of the Fox01 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins
复制标题
DOI：
10.1073/pnas.0405454101
复制
发表时间：
2004-09-14
影响因子：
11.1
通讯作者：
Vogt, PK
中科院分区：
文献类型：
--
作者：
Aoki, M;Hao, J;Vogt, PK
P3 k癌蛋白[1A类磷酸肌醇3-激酶（PI 3 K）催化亚基p110 α的同源物]及其下游效应物Akt在鸡胚成纤维细胞（CEF）培养物中诱导致癌转化。翼状螺旋转录因子FoxO 1是一种生长衰减和促凋亡蛋白，并作为Akt的底物。在这里，我们表明，FoxO 1的表达是组成性抑制CEF转化P3 K或Akt。FoxO 1蛋白水平在血清饥饿的正常CEF中很高，但血小板衍生生长因子治疗诱导FoxO 1快速磷酸化和消失。PI 3 K抑制剂或蛋白酶体抑制剂lactacystin干扰这一过程。这些数据表明，磷酸化依赖性降解FoxO 1的蛋白酶体的P3 k和Akt的致癌转化中发挥了作用。含有果蝇Engrailed蛋白阻遏结构域的FoxO 1显性负突变体诱导CEF部分致癌转化并干扰FoxO 1依赖的转录激活FoxG 1癌蛋白还抑制FoxO 1的转录激活。尽管通过不同的机制抑制FoxO 1，但似乎是PI 3 K和FoxG 1致癌途径的共同点。
The P3k oncoprotein [homolog of the catalytic subunit p110alpha of class 1A phosphoinositicle 3-kinase (PI3K)] and its downstream effector Akt induce oncogenic transformation in cultures of chicken embryo fibroblasts (CEF). The winged helix transcription factor FoxO1 is a growth-attenuating and proapoptotic protein and serves as a substrate of Akt. Here we show that FoxO1 expression is constitutively suppressed in CEF transformed by P3k or Akt. The FoxO1 protein level is high in serum-starved normal CEF, but plate let-derived growth factor treatment induces rapid phosphorylation and disappearance of FoxO1. PI3K inhibitors or the proteasome inhibitor lactacystin interfere with this process. These data suggest that phosphorylation-dependent degradation of FoxO1 by means of proteasomes plays a role in oncogenic transformation by P3k and Akt. A dominant negative mutant of FoxO1 containing the repressor domain of the Drosophila Engrailed protein induces partial oncogenic transformation of CEF and interferes with FoxO1-dependent transcriptional activation. The FoxG1 oncoprotein also inhibits transcriptional activation by FoxO1. Inhibition of FoxO1, albeit by different mechanisms, appears to be a common denominator of the PI3K and FoxG1 oncogenic pathways.