An integrated understanding of the physiological response to elevated extracellular phosphate.
An integrated understanding of the physiological response to elevated extracellular phosphate.
复制标题
DOI：
10.1002/jcp.24312
复制
发表时间：
2013-07
影响因子：
5.6
通讯作者：
Beck, George R., Jr.
中科院分区：
文献类型：
--
作者：
Camalier, Corinne E.;Yi, Ming;Yu, Li-Rong;Hood, Brian L.;Conrads, Kelly A.;Lee, Young Jae;Lin, Yiming;Garneys, Laura M.;Bouloux, Gary F.;Young, Matthew R.;Veenstra, Timothy D.;Stephens, Robert M.;Colburn, Nancy H.;Conrads, Thomas P.;Beck, George R., Jr.
最近的研究表明，血清磷酸盐水平的变化会影响与衰老相关的病理状态，如癌症，骨代谢和心血管功能，即使在肾功能正常的个体中也是如此。其原因才刚刚开始阐明，但很可能是内分泌，旁分泌，自分泌和细胞自主效应的组合。我们已经使用了一个综合的定量生物学方法，结合转录组学和蛋白质组学，以确定一个多相，细胞外磷酸盐诱导的，前成骨细胞以及原代人类和小鼠间充质基质细胞的信号网络。我们确定了一个快速的促有丝分裂反应刺激磷酸盐升高，导致诱导立即早期基因，包括c-fos。激活机制需要FGF受体信号传导，然后刺激N-ras和激活AP-1和血清应答元件。独特的长期反应还需要FGF受体信号传导，并导致N-ras激活和基因表达以及参与基质调节、钙化和血管生成的蛋白质分泌。通过添加FGF 23肽协同增强晚期应答。中间阶段导致氧化磷酸化和ATP产生增加，并且是晚期反应所必需的，提供了阶段之间的功能联系。总的来说，结果定义升高的磷酸盐，作为有丝分裂原，并定义磷酸盐刺激增殖和基质调节的特定机制。我们的方法提供了一个全面的理解细胞对细胞外磷酸盐升高的反应，在功能上连接时间协调的信号传导，转录和代谢事件与长期细胞行为的变化。
Recent studies have suggested that changes in serum phosphate levels influence pathological states associated with aging such as cancer, bone metabolism, and cardiovascular function, even in individuals with normal renal function. The causes are only beginning to be elucidated but are likely a combination of endocrine, paracrine, autocrine, and cell autonomous effects. We have used an integrated quantitative biology approach, combining transcriptomics and proteomics to define a multi-phase, extracellular phosphate-induced, signaling network in pre-osteoblasts as well as primary human and mouse mesenchymal stromal cells. We identified a rapid mitogenic response stimulated by elevated phosphate that results in the induction of immediate early genes including c-fos. The mechanism of activation requires FGF receptor signaling followed by stimulation of N-ras and activation of AP-1 and serum response elements. A distinct long-term response also requires FGF receptor signaling and results in N-ras activation and expression of genes and secretion of proteins involved in matrix regulation, calcification, and angiogenesis. The late response is synergistically enhanced by addition of FGF23 peptide. The intermediate phase results in increased oxidative phosphorylation and ATP production and is necessary for the late response providing a functional link between the phases. Collectively, the results define elevated phosphate, as a mitogen and define specific mechanisms by which phosphate stimulates proliferation and matrix regulation. Our approach provides a comprehensive understanding of the cellular response to elevated extracellular phosphate, functionally connecting temporally coordinated signaling, transcriptional, and metabolic events with changes in long-term cell behavior.
登录
查看更多内容
影响因子：
5.6
作者：
BARSH, GS;GREENBERG, DB;CUNNINGHAM, DD
通讯作者：
CUNNINGHAM, DD
DOI：
10.1165/rcmb.2005-0477oc
发表时间：
2006-11-01
影响因子：
6.4
作者：
Chang, Seung-Hee;Yu, Kyeong Nam;Cho, Myung-Haing
通讯作者：
Cho, Myung-Haing
DOI：
10.1158/1940-6207.capr-09-0068
发表时间：
2010-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Camalier CE;Young MR;Bobe G;Perella CM;Colburn NH;Beck GR Jr
通讯作者：
Beck GR Jr
影响因子：
4.2
作者：
ARENANDER, AT;LIM, RW;HERSCHMAN, HR
通讯作者：
HERSCHMAN, HR
影响因子：
4.8
作者：
Beck, Laurent;Leroy, Christine;Friedlander, Gerard
通讯作者：
Friedlander, Gerard