Protein kinase C epsilon regulation of translocator protein (18 kDa) Tspo gene expression is mediated through a MAPK pathway targeting STAT3 and c-Jun transcription factors.
Protein kinase C epsilon regulation of translocator protein (18 kDa) Tspo gene expression is mediated through a MAPK pathway targeting STAT3 and c-Jun transcription factors.
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DOI：
10.1021/bi100020e
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发表时间：
2010-06-15
期刊：
影响因子：
2.9
通讯作者：
Papadopoulos V
中科院分区：
文献类型：
--
作者：
Batarseh A;Li J;Papadopoulos V
转位蛋白TSPO是一种18 kDa的蛋白，参与多种细胞功能，在分泌和腺体组织中高度表达，尤其在类固醇生成细胞中表达。在某些病理情况下，如某些癌症和神经疾病，TSPO的表达会发生变化。在寻找调节Tspo表达的因素方面，我们最近发现，在类固醇生成细胞中，Tspo的高水平可能是由于蛋白激酶Cε(PKCε)的高结构性表达，而蛋白激酶Cε的佛波醇-12-肉豆蔻酸酯13-乙酸酯(PMA)激活可能通过激活蛋白1(Activator Protein 1)驱动非类固醇生成细胞中Tspo的诱导表达。本研究旨在明确PKCE调控TSPO基因表达的信号转导途径。在富含TSPO的类固醇合成细胞(MA-10 Leydig)中，MEK1/2的特异性抑制剂U0126，而不是NF-κB抑制剂，降低了基础的TSPO启动子活性，以及在缺乏TSPO的非类固醇生成细胞(NIH3T3成纤维细胞)中，降低了基础和PMA诱导的TSPO启动子水平。AP1和信号转导与转录激活3(STAT3)在TSPO启动子上有结合部位，是蛋白激酶Cε和MAPK(Raf-1-ERK1/2)通路的下游靶点。PKCE过表达可诱导NIH-3T3细胞中STAT3的磷酸化，而PKCE基因敲除则可降低间质细胞中STAT3和c-jun的磷酸化水平。MEK1/2、ERK2、c-jun和STAT3基因敲除降低了间质细胞中TSPO的mRNA和蛋白水平。此外，Raf-1还降低了同一细胞中TSPO的mRNA水平。MEK1/2、c-jun和STAT3基因敲除也降低了基础水平和PMA诱导的NIH-3T3细胞中TSPO的mRNA水平。综上所述，这些结果表明，PKCE通过MAPK(Raf-1-MEK1/2-ERK1/2)信号转导途径调节TSPO基因的表达，至少部分通过c-jun和STAT3转录因子发挥作用。
Translocator protein TSPO is an 18 kDa protein implicated in numerous cell functions and is highly expressed in secretory and glandular tissues, especially in steroidogenic cells. TSPO expression is altered in pathological conditions such as certain cancers and neurological diseases. In search of the factors regulating Tspo expression, we recently showed that high levels of TSPO in steroidogenic cells may be due to high constitutive expression of protein kinase Cε (PKCε), while phorbol-12-myristate 13-acetate (PMA) activation of PKCε drives inducible TSPO expression in non-steroidogenic cells, likely through activator protein 1 (AP1). In this study, we aimed to identify the signal transduction pathway through which PKCe regulates Tspo gene expression. The MEK1/2 specific inhibitor U0126, but not NFκB inhibitors, reduced basal Tspo promoter activity in TSPO-rich steroidogenic cells (MA-10 Leydig), as well as basal and PMA-induced Tspo promoter levels in TSPO-poor non-steroidogenic cells (NIH-3T3 fibroblasts). AP1 and signal transducer and activation of transcription 3 (STAT3) have binding sites in the Tspo promoter and are downstream targets of PKCε and MAPK (Raf-1 -ERK1/2) pathways. PKCe overexpression induced STAT3 phosphorylation in NIH-3T3 cells, while PKCe knockdown reduced STAT3 and c-Jun phosphorylation in Leydig cells. MEK1/2, ERK2, c-Jun, and STAT3 knockdown reduced Tspo mRNA and protein levels in Leydig cells. Additionally, Raf-1 reduced Tspo mRNA levels in the same cells. MEK1/2, c-Jun, and STAT3 knockdown also reduced basal as well as PMA-induced Tspo mRNA levels in NIH-3T3 cells. Together, these results demonstrate that PKCe regulates Tspo gene expression through a MAPK (Raf-1-MEK1/2-ERK1/2) signal transduction pathway, acting at least in part through c-Jun and STAT3 transcription factors.
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