REGULATION OF MITOGENESIS AND APOPTOSIS BY G PROTEINS

丝裂原活化蛋白激酶途径，包括细胞外 信号调节激酶（ERK）通路和c-Jun激酶（JNK） 途径，由生长因子、细胞因子和G蛋白激活 偶联受体 基于氨基酸序列相似性，α 12 和α 13属于不同类别的G蛋白α亚单位。 的 这种距离G蛋白类的特异性信号通路，包括 直接与α 12相互作用的直接效应分子， 第13章未知 我的初步研究表明， 组成型激活的α 12和α 13诱导 哺乳动物细胞（NIH 3 T3）和大鼠-1）。 在NIH 3 T3和Rat-1细胞中， α 12和α 13增加细胞生长速率， ERK通路的激素刺激。 相反，在COS-7细胞中， α 12和α 13诱导细胞凋亡，α 12和α 13 以Ras和Raf-independent方式抑制ERK通路。 这 该提案集中于将α 12和α 13偶联到 ERK和JNK通路的调节，以了解 G12和G13以及alpha 12和alpha 13的效应途径在 有丝分裂和凋亡的调节。 实验将：i. 表征与α 12直接相互作用的效应分子， alpha 13和阐明alpha 12和 α 13调节ERK途径; ii. 确定阿尔法12和 α 13在有丝分裂中使用ERK或JNK途径， 每种途径中的蛋白质对于有丝分裂是必需和足够的; iii. 确定α 12和α 13是否使用ERK或JNK通路 以及每种途径中的哪种蛋白质是必需的， 足以进行细胞凋亡; iv. Bcl-2和Bax这两种 控制程序性细胞死亡，调节α 12诱导的凋亡 和α 13; V.鞘氨醇和鞘氨醇-1磷酸（其 调节有丝分裂）和神经酰胺（调节凋亡）调节 有丝分裂和细胞凋亡诱导的α 12和α 13。

Mitogen-activated protein kinase pathways, including the extracellular signal-regulated kinase (ERK) pathway and the c-Jun kinase (JNK) pathway, are activated by growth factors, cytokines, and G-protein coupled receptors. Based on amino acid sequence similarities, alpha12 and alpha13 belong to a distinct class of G protein alpha sub-units. The specific signaling pathways for this distance G protein class, including immediate effector molecules interacting directly with alpha12 and alpha13, remain unknown. My preliminary studies indicate that constitutively activated alpha12 and alpha13 induce mitogenesis of mammalian cells (NIH3T3) and Rat-1). In NIH3T3 and Rat-1 cells, alpha12 and alpha13 increase cellular growth rate and potentiate hormonal stimulation of the ERK pathway. In contrast, in COS-7 cells, alpha12 and alpha13 induce apoptosis and both alpha12 and alpha13 inhibit the ERK pathway in a Ras- and Raf-independent manner. This proposal focuses on the mechanisms that couple alpha12 and alpha13 to the regulation of the ERK and JNK pathways to understand functions of G12 and G13 and the effector pathways of alpha12 and alpha13 in the regulation of mitogenesis and apoptosis. Experiments will: i. characterize the effector molecules that interact directly with alpha12 and alpha13 and elucidate the molecular mechanisms by which alpha12 and alpha13 regulate ERK pathway; ii. Determine whether alpha 12 and alpha13 employ ERK or JNK pathways in the mitogenesis and which protein in each pathway is necessary and sufficient for mitogenesis; iii. Determine whether alpha12 and alpha13 employ ERK or JNK pathways in the apoptosis and which protein in each pathway is necessary and sufficient for apoptosis; iv. How Bcl-2 and Bax, two proteins that control programmed cell death, regulate apoptosis induced by alpha12 and alpha13; v. how sphingosine and sphingosine-1 phosphate (that regulate mitogenesis) and ceramide (that regulate apoptosis) regulate mitogenesis and apoptosis induced by alphas12 and alpha13.