Protein Kinase Cε Regulation of Translocator Protein (18 kDa) Tspo Gene Expression Is Mediated through a MAPK Pathway Targeting STAT3 and c-Jun Transcription Factors
- 16 May 2010
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 49 (23), 4766-4778
- https://doi.org/10.1021/bi100020e
Abstract
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 nonsteroidogenic cells, likely through activator protein 1 (AP1). In this study, we aimed to identify the signal transduction pathway through which PKCε 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 nonsteroidogenic 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. PKCε overexpression induced STAT3 phosphorylation in NIH-3T3 cells, while PKCε 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 PKCε 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.This publication has 34 references indexed in Scilit:
- Translocator protein (18 kDa) TSPO: An emerging therapeutic target in neurotraumaExperimental Neurology, 2009
- Phorbol-12-myristate 13-Acetate Acting through Protein Kinase Cε Induces Translocator Protein (18-kDa) Tspo Gene ExpressionBiochemistry, 2008
- Amino Acid Residues Required for Physical and Cooperative Transcriptional Interaction of STAT3 and AP-1 Proteins c-Jun and c-FosMolecular and Cellular Biology, 2007
- Protein kinase Cε interacts with Stat3 and regulates its activation that is essential for the development of skin cancerMolecular Carcinogenesis, 2007
- The Role of Ets Transcription Factors in the Basal Transcription of the Translocator Protein (18 kDa)Biochemistry, 2007
- Ras/ERK1/2-mediated STAT3 Ser727 Phosphorylation by Familial Medullary Thyroid Carcinoma-associated RET Mutants Induces Full Activation of STAT3 and Is Required for c-fos Promoter Activation, Cell Mitogenicity, and TransformationPublished by Elsevier BV ,2007
- Possible role of duration of PKC-induced ERK activation in the effects of agonists and phorbol esters on DNA synthesis in panc-1 cellsJournal of Cellular Biochemistry, 2006
- Prooxidant Effects of NGF Withdrawal and MEK Inhibition in Sympathetic NeuronsAntioxidants and Redox Signaling, 2003
- Synergistic Activity of STAT3 and c-Jun at a Specific Array of DNA Elements in the α2-Macroglobulin PromoterPublished by Elsevier BV ,2001
- AP1, a composite transcription factor implictted in abnormal growth controlProgress in Growth Factor Research, 1989