Abstract
DJ-1 is an oncogene and also causative gene for familial Parkinson’s disease. DJ-1 has multiple functions, including transcriptional regulation. DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found that the cholecystokinin (CCK) gene is a transcriptional target gene for DJ-1. CCK is a peptide hormone and plays roles in contraction of the gallbladder and in promotion of secretion of pancreatic fluid. CCK is co-localized with dopamine in the substantia nigra to regulate release of dopamine. Reduced expression of CCK mRNA was observed in DJ-1-knockdown cells. The Ras-responsive element (RRE) and Sp1 site were essential for promoter activity, and DJ-1 stimulated promoter activity by binding to RRE-binding protein 1 (RREBP1). The complex of DJ-1 with RREB1 but not with Sp1 bound to the RRE. Furthermore, the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed. This is the first report showing that DJ-1 participates in peptide hormone synthesis.
Highlights
The DJ-1 gene has been identified by us as a novel oncogene that transforms NIH3T3 cells in cooperation with the activated ras gene [1] and was later found to be a causative gene for familial Parkinsons disease park7 [2]
We found that DJ-1 positively regulates CCK gene expression at the transcriptional level through association of RREB1 on the Ras-responsive element (RRE) located in the CCK promoter
Reduced expression of the CCK gene was observed in two lines of DJ-1knockdown cells (Fig. 1), and the reduced CCK level was found in the serum from DJ-1-knockout mice compared to that in wild-type mice (Fig. 5)
Summary
The DJ-1 gene has been identified by us as a novel oncogene that transforms NIH3T3 cells in cooperation with the activated ras gene [1] and was later found to be a causative gene for familial Parkinsons disease park7 [2]. DJ-1 has multiple functions, including transcriptional regulation [6,7,8,9,10,11,12,13,14,15]. DJ1 binds to various transcription factors, including inhibitors for androgen receptor [6,7], p53 [8,13,15], polypyrimidine tractbinding protein-associated splicing factor (PSF) [9], Keap, an inhibitor for nuclear factor erythroid-2 related factor 2 (Nrf2) [10], and sterol regulatory element binding protein (SREBP) [16] to modulate their transcriptional activity, resulting in various effects on cell functions. We found by using a cell culture system that DJ-1 stimulates expression of the CCK gene at the transcriptional level by association with RREB1 and that the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed
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