权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CROSSTALK BETWEEN CAMP AND RAS IN ENDOCRINE CELLS

内分泌细胞中 CAMP 和 RAS 之间的串扰

基本信息

批准号：
6380045
负责人：
JUDY L MEINKOTH
金额：
$ 10.61万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2002-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (Taken from the applicant's abstract) Because cells respond to a wide array of signals received at the cell surface, their ability to integrate and respond appropriately to these signals is essential. One of the best studied examples of signaling crosstalk is the interplay between Ras- and cAMP-mediated pathways. Cyclic AMP inhibits proliferation in many cells, in part through uncoupling Ras from one of its downstream effectors, Raf-1. Elevations in cAMP, however, are not universally growth inhibitory. In thyrocytes, pituitary somatotrophs and other cells, cAMP stimulates proliferation. We discovered that thyrotropin (TSH) stimulates proliferation through a novel pathway involving both Ras and the cAMP-dependent protein kinase, but not the well described downstream effectors of Ras, Raf-1 and the mitogen-activated protein kinase cascade. The effectors used by Ras in the presence of TSH and elevated cAMP levels remain to be elucidated, but may include phosphatidylinositol 3-kinase, the isoform of protein kinase C, and other small G proteins. It is the goal of these studies to elucidate those molecules which transduce TSH-stimulated mitogenic signals, including the identification of novel Ras effectors, and the sites of interaction between Ras- and cAMP-mediated pathways. Using microinjection of purified signaling molecules and highly specific inhibitors, the biological activity of a panel of Ras mutants defective in various effector interactions will be assessed. Ras-overexpressing thyroid cells will be screened for novel proteins that bind to GTP-bound Ras. Other molecules proposed to function as Ras effectors will be assessed for growth-stimulating activity in the thyrocyte. Together these approaches will provide insight into novel Ras-mediated signaling pathways active in thyroid cells. Once these molecules are identified, we will test their activity in growth stimulation in other epithelial cells, including pituitary somatotrophs and mammary epithelial cells. Ras gene activation and the constitutive activation of cAMP-mediated signaling pathways have been identified in human thyroid and pituitary cancer. The elucidation of the molecular components of, and interactions between these pathways may identify novel targets for therapeutic intervention. My long term career goal is to identify the molecular components of growth-signaling pathways in a variety of epithelial cell types in a challenging academic environment. The University of Pennsylvania provides an exciting and rich research environment in which to pursue these studies.

描述（摘自申请人摘要）因为细胞会对细胞接收到的大量信号做出反应表面，他们的能力，整合和适当地应对这些信号是必不可少的。一个被研究得最好的信号例子串扰是Ras和cAMP介导的途径之间的相互作用。环状 AMP抑制许多细胞的增殖，部分是通过解偶联Ras 来自其下游效应子Raf-1 然而，cAMP的升高，并不普遍具有生长抑制作用。在甲状腺细胞、垂体在生长激素细胞和其他细胞中，cAMP刺激增殖。我们发现促甲状腺激素（TSH）通过一种新的途径刺激增殖，涉及Ras和cAMP依赖性蛋白激酶，但不包括描述了Ras、Raf-1和促分裂原激活的蛋白激酶级联反应促甲状腺激素存在时Ras使用的效应物和cAMP水平升高仍有待阐明，但可能包括磷脂酰肌醇3-激酶，蛋白激酶C的同种型，以及其他小G蛋白这些研究的目标是阐明那些与细胞凋亡有关的分子。 TSH刺激的促有丝分裂信号，包括新Ras的鉴定效应子，以及Ras和cAMP介导的途径。使用显微注射纯化的信号分子和高度特异性抑制剂，一组Ras突变体的生物活性将评估各种效应物相互作用的缺陷。 Ras过表达的甲状腺细胞将被筛选出新的蛋白质，与GTP结合的Ras结合。其他被认为是Ras效应子的分子将评估甲状腺细胞中的生长刺激活性。一起这些方法将提供对新型Ras介导的信号传导的深入了解，甲状腺细胞中的活性通路。一旦这些分子被识别，我们将测试它们在其他上皮细胞中的生长刺激活性，包括垂体生长激素细胞和乳腺上皮细胞。 Ras基因 cAMP介导的信号传导的激活和组成性激活已经在人甲状腺癌和垂体癌中鉴定了这些途径。的阐明这些分子的分子组成及其相互作用，通路可以识别治疗干预的新靶点。我的长期职业目标是鉴定生长信号通路在各种上皮细胞类型，具有挑战性的学术环境。宾夕法尼亚大学提供一个令人兴奋的和丰富的研究环境，在其中进行这些研究。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential effects of acute and chronic exposure to interferon-gamma on cyclic adenosine 3',5'-monophosphate response element-regulated gene expression.

急性和慢性暴露于干扰素-γ 对环腺苷 3,5-单磷酸反应元件调节基因表达的不同影响。

DOI：
10.1210/endo.141.2.7301
发表时间：
2000
期刊：
Endocrinology.
影响因子：
0
作者：
Saavedra,AP;Cass,LA;Prendergast,GV;Meinkoth,JL
通讯作者：
Meinkoth,JL

Performance of modified Igls criteria to evaluate islet autograft function after total pancreatectomy with islet autotransplantation - a retrospective study.

DOI：
10.1111/tri.13762
发表时间：
2021-01
期刊：
Transplant international : official journal of the European Society for Organ Transplantation
影响因子：
0
作者：
McEachron KR;Yang Y;Hodges JS;Beilman GJ;Kirchner VA;Pruett TL;Chinnakotla S;Hering BJ;Bellin MD
通讯作者：
Bellin MD

Differential effects of cyclic adenosine 3',5'-monophosphate on p70 ribosomal S6 kinase.

环腺苷 3,5-单磷酸对 p70 核糖体 S6 激酶的不同影响。