Graded mitogen-activated protein kinase activity precedes switch-like c-fos induction in mammalian cells
Graded mitogen-activated protein kinase activity precedes switch-like c-fos induction in mammalian cells
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DOI：
10.1128/mcb.25.11.4676-4682.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
MacKeigan, JP;Murphy, LO;Blenis, J
丝裂原活化蛋白激酶(MAPK)通路是一个进化上保守的信号模块，在各种生理环境中控制着重要的细胞命运决定。在非洲爪哇卵母细胞成熟过程中，MAPK级联反应会将孕酮增加的刺激转化为开关样的、要么全有要么全无的反应。虽然这种开关样行为的重要性在文献中得到了广泛的讨论，但尚不清楚哺乳动物细胞中的MAPK通路是表现出开关样反应还是分级反应。在这项研究中，我们使用流式细胞术和免疫荧光技术对瑞士3T3成纤维细胞中的MAPK信号进行单细胞测量。与非洲爪哇卵母细胞的情况相比，我们发现单个哺乳动物细胞中ERK的激活并不是超敏感的，并且显示出对激动剂浓度变化的分级反应。因此，保守的MAPK信号模块在不同的细胞环境中表现出不同的系统级特性。此外，分级的ERK反应在即刻-早期基因诱导和细胞周期进展的水平上转化为更具开关性质的行为。因此，虽然MAPK信号参与了非洲爪哇卵母细胞成熟和哺乳动物成纤维细胞增殖的全有或全无细胞命运的决定，但在这两个系统中，导致细胞反应的开关性质的潜在机制是不同的，在哺乳动物成纤维细胞中，该机制似乎位于激酶级联的下游。
The mitogen-activated protein kinase (MAPK) pathway is an evolutionarily conserved signaling module that controls important cell fate decisions in a variety of physiological contexts. During Xenopus oocyte maturation, the MAPK cascade converts an increasing progesterone stimulus into a switch-like, all-or-nothing response. While the importance of such switch-like behavior is widely discussed in the literature, it is not known whether the MAPK pathway in mammalian cells exhibits a switch-like or graded response. For this study, we used flow cytometry and immunofluorescence to generate single-cell measurements of MAPK signaling in Swiss 3T3 fibroblasts. In contrast to the case in Xenopus oocytes, we found that ERK activation in individual mammalian cells is not ultrasensitive and shows a graded response to changes in agonist concentration. Thus, the conserved MAPK signaling module exhibits different systems-level properties in different cellular contexts. Furthermore, the graded ERK response was converted into a more switch-like behavior at the level of immediate-early gene induction and cell cycle progression. Thus, while MAPK signaling is involved in all-or-nothing cell fate decisions for both Xenopus oocyte maturation and mammalian fibroblast proliferation, the underlying mechanisms responsible for the switch-like nature of the cellular responses are different in these two systems, with the mechanism appearing to fie downstream of the kinase cascade in mammalian fibroblasts.