cAMP Signaling in Sympathoadrenal Cell Development

交感肾上腺细胞发育中的 cAMP 信号转导

基本信息

批准号：
6818091
负责人：
Ourania M. Andrisani
金额：
$ 30.38万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2007-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposed studies addresses the interplay of the cAMP and BMP-2 signaling pathways in determining the differentiation of Neural Crest (NC) cells to the sympathoadrenal (SA) lineage, employing primary NC cultures. In separate studies, bone morphogenetic proteins (BMP-2, 4 and 7) and cAMP elevating agents were shown to stimulate SA cell development, characterized by the expression of tyrosine hydroxylase (TH), dopamineB-hydroxylase (DBH) and the synthesis of catecholamines (CA). Only recently, studies from our laboratory demonstrated that the cAMP signaling pathway modulates both positive and negative signals which influence SA cell development. Specifically, moderate activation of cAMP signaling, in synergy with BMP-2, promotes SA cell development and induces the expression of the SA lineage-determining gene Phox2a. By contrast, robust activation of cAMP signaling opposes, even in the presence of BMP-2, SA cell development and blocks the expression of the SA lineage-determining genes ASH-I and Phox2a. The objectives of the proposed studies investigate the molecular mechanisms by which cAMP acts as a bimodal switch on SA cell development. Aim 1 addresses the hypothesis that low-level cAMP signaling synergizes transcriptionally with BMP-2 signaling at the phox2a gene promoter, via synergistic interactions occurring between the transcription factors ASH-i and CREB, and the co-activator protein CBP. Aim 2 addresses the hypothesis that the antagonistic effect of high-level cAMP signaling on SA cell development involves the activation of the MAPK pathway, effecting the inhibition of the BMP-2-activated transactivators SMADs. The Specific Aims are: Aim 1: To determine whether the synergistic effect between BMP-2 and low-level activation of cAMP signaling, on SA cell development and Phox2a expression, is linked to the transcriptional function of the cAMP pathway. Aim 2: To define the mechanism of the antagonistic effect of high-level activation of cAMP signaling on the BMP-2 mediated ASH-I gene expression and SA cell development.

描述（由申请人提供）：拟议研究的长期目标解决 cAMP 和 BMP-2 信号通路在确定中的相互作用神经嵴 (NC) 细胞向交感肾上腺 (SA) 细胞的分化谱系，采用初级 NC 文化。在单独的研究中，骨形态发生蛋白质（BMP-2、4 和 7）和 cAMP 升高剂可刺激 SA 细胞发育，以酪氨酸羟化酶（TH）的表达为特征，多巴胺 B-羟化酶 (DBH) 和儿茶酚胺 (CA) 的合成。仅有的最近，我们实验室的研究表明，cAMP 信号传导途径调节影响 SA 细胞的正信号和负信号发展。具体来说，适度激活 cAMP 信号传导，协同作用与 BMP-2 结合，促进 SA 细胞发育并诱导 SA 的表达谱系决定基因 Phox2a。相比之下，cAMP 的强烈激活即使存在 BMP-2，信号传导也会阻碍 SA 细胞的发育和阻断 SA 谱系决定基因 ASH-I 和 Phox2a 的表达。拟议研究的目的是通过以下方式调查分子机制其中 cAMP 充当 SA 细胞发育的双模式开关。目标 1 解决了假设低水平的 cAMP 信号在转录上与通过协同相互作用，phox2a 基因启动子上的 BMP-2 信号传导发生在转录因子 ASH-i 和 CREB 之间，共激活蛋白CBP。目标 2 提出了以下假设：对抗性高水平 cAMP 信号传导对 SA 细胞发育的影响涉及 MAPK 通路的激活，影响 BMP-2 激活的抑制反式激活剂 SMAD。具体目标是：目标 1：确定是否 BMP-2 和 cAMP 信号传导低水平激活之间的协同作用， SA 细胞发育和 Phox2a 表达与转录相关 cAMP 通路的功能。目标 2：定义机制高水平激活 cAMP 信号对 BMP-2 的拮抗作用介导 ASH-I 基因表达和 SA 细胞发育。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Time-dependent activation of Phox2a by the cyclic AMP pathway modulates onset and duration of p27Kip1 transcription.

环 AMP 通路对 Phox2a 的时间依赖性激活可调节 p27Kip1 转录的起始时间和持续时间。

DOI：
10.1128/mcb.01928-08
发表时间：
2009
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
Shin,MinHwa;Mavila,Nirmala;Wang,Wen-Horng;VegaAlvarez,Sasha;Hall,MarkC;Andrisani,OuraniaM
通讯作者：
Andrisani,OuraniaM

Down-regulation of RE-1 silencing transcription factor (REST) in advanced prostate cancer by hypoxia-induced miR-106b~25.

DOI：
10.1016/j.yexcr.2013.09.020
发表时间：
2014-01-15
期刊：
EXPERIMENTAL CELL RESEARCH
影响因子：
3.7
作者：
Liang, Hongzi;Studach, Leo;Hullinger, Ronald L.;Xie, Jun;Andrisani, Ourania M.
通讯作者：
Andrisani, Ourania M.