Monoarnine oxidase A and repressor R1 are involved in apoptotic signaling pathway
Monoarnine oxidase A and repressor R1 are involved in apoptotic signaling pathway
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DOI：
10.1073/pnas.0601515103
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发表时间：
2006-07-18
影响因子：
11.1
通讯作者：
Shih, Jean C.
中科院分区：
文献类型：
--
作者：
Ou, Xiao-Ming;Chen, Kevin;Shih, Jean C.
单胺氧化酶A（MAO A）降解血清素、去甲肾上腺素和多巴胺，并产生可导致神经元细胞死亡的活性氧。我们以前曾报道过一种新的转录因子R1（RAM 2/CDCA 7 L/JP 02）抑制MAOA启动子和酶活性。本研究报道了MAO-A和RI在细胞凋亡和增殖中的作用。我们发现，在血清饥饿诱导的细胞凋亡，p38激酶，MAO A，caspase-3的增加，而Bcl-2和R1减少。使用p38激酶抑制剂、R1过表达和MAO A抑制剂，我们已经表明MAO A和R1在p38激酶和Bcl-2的下游，但在caspase-3的上游。MAO A的抑制防止细胞凋亡。这一观点进一步得到以下发现的支持：与WT相比，在来自MAO A缺陷小鼠的皮质脑细胞中，血清饥饿诱导的细胞凋亡减少。此外，我们发现在血清存在下，MAO A和R1参与c-Myc诱导的增殖信号通路。免疫沉淀和免疫组织化学实验表明，癌基因c-Myc与R1共定位，并诱导R1基因的表达。使用R1过表达，R1小干扰RNA和MAO A抑制剂，我们发现R1和MAO A作用于细胞周期蛋白D1和E2 F1的上游。总之，本研究证实了MAO A及其阻遏物R1在凋亡信号通路中的功能。
Monoamine oxidase A (MAO A) degrades serotonin, norepinephrine, and dopamine and produces reactive oxygen that may cause neuronal cell death. We have previously reported that a novel transcription factor R1 (RAM2/CDCA7L/JP02) inhibits the MAO A promoter and enzymatic activities. This study reports the roles of MAO A and RI in apoptosis and proliferation. We have found that in serum starvation-induced apoptosis, p38 kinase, MAO A, and caspase-3 were increased, whereas Bcl-2 and R1 were reduced. Using a p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, we have shown that MAO A and R1 are downstream of p38 kinase and Bcl-2, but upstream of caspase-3. Inhibition of MAO A prevents cell apoptosis. This notion was further supported by the finding that serum starvation-induced apoptosis is reduced in cortical brain cells from MAO A-deficient mice compared with WT. In addition, we found that MAO A and R1 are involved in the c-Myc-induced proliferative signaling pathway in the presence of serum. Immunoprecipitation and immunohistochemistry experiments indicate that the oncogene c-Myc colocalizes with R1 and induces R1 gene expression. Using R1 overexpression, R1 small interfering RNA, and a MAO A inhibitor, we found that R1 and MAO A act upstream of cyclin D1 and E2F1. In summary, this study demonstrates the functions of MAO A and its repressor R1 in apoptotic signaling pathways.