DJ-1 upregulates tyrosine hydroxylase gene expression by activating its transcriptional factor Nurr1 via the ERK1/2 pathway.
Loss-of-function DJ-1 mutations have been linked to autosomal recessive early-onset Parikinsonism. However, the putative function of DJ-1 is not completely understood. Previous studies indicate that DJ-1 overexpression results in upregulation of the tyrosine hydroxylase gene. The mechanism by which DJ-1 affects tyrosine hydroxylase expression remains elusive. In the present study, we show that DJ-1 overexpression induces ERK1/2 activation, along with increased tyrosine hydroxylase expression. The L166P DJ-1 mutant, which has been identified as being responsible for familial Parkinsonism, did not have this effect. Moreover, suppression of ERK1/2 phosphorylation by the pharmacological inhibitor U0126 partially abolished the regulating effect of DJ-1 on tyrosine hydroxylase. Nurr1, a transcriptional factor for tyrosine hydroxylase, can be phosphorylated by ERK1/2 and translocate to the nucleus, where it is activated. Thus, we measured nuclear translocation of Nurr1. Confocal microscopy and Western blotting revealed that Nurr1 translocated to the nucleus and was activated by overexpression of wild-type DJ-1, but not of its L166P mutant. Knockdown of Nurr1 gene expression abolished the effect on tyrosine hydroxylase induced by DJ-1. Taken together, these data suggest that DJ-1 upregulates tyrosine hydroxylase expression by activating its transcription factor Nurr1 via the ERK1/2 pathway.
Beijing Institute for Neuroscience, Capital Medical University, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
Lingling
L
Lu
Xiaohong
X
Sun
Yujun
Y
Liu
Huanying
H
Zhao
Shasha
S
Zhao
Hui
H
Yang
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D000071617:Protein Deglycase DJ-1; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D014178:Translocation, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D002070:Butadienes; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D015513:Oncogene Proteins; C113580:U 0126; D014446:Tyrosine 3-Monooxygenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1