Journal
BIOCHEMICAL JOURNAL
Volume 438, Issue -, Pages 93-101Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20101840
Keywords
dual leucine zipper-bearing kinase (DLK); neuron; peroxisome-proliferator-activated receptor gamma (PPAR gamma); retinoid X receptor (RXR); rosiglitazone; transcriptional regulation
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Funding
- Natural Science and Engineering Research Council of Canada [138068]
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DLK (dual leucine zipper-bearing kinase) is a key regulator of development, cell differentiation and apoptosis. Interestingly, recent studies have shown that DLK expression is up-regulated in 3T3-L1 cells induced to differentiate into adipocytes and that DLK knockdown impairs the expression of PPAR gamma (peroxisome-proliferator-activated receptor gamma), a master regulator of adipogenesis. Because the PPAR gamma agonist rosiglitazone was found to increase DLK expression in 3T3-L1 cells, we hypothesized that PPAR gamma is required for the transcriptional activation of the DLK gene. To test this hypothesis, we first examined the effects of pharmacological inhibition or shRNA (small-hairpin RNA)-mediated depletion of PPAR gamma on DLK accumulation in 3T3-L1 cells undergoing differentiation. :In addition to blocking adipocyte conversion of 3T3-L1 cells, inhibition of PPAR gamma suppressed DLK expression at both the mRNA and protein levels. Moreover, supporting a role for PPAR gamma in DLK regulation, two potential PPAR gamma-binding sites identified by bioinformatic tools at positions -611 and -767 upstream of the DLK gene transcriptional start site were shown by electrophoretic mobility-shift assay and chromatin immunoprecipitation to bind PPAR gamma and its essential heterodimer partner retinoid X receptor as differentiation proceeds. Collectively, these results show that DLK is a novel transcriptional target of PPAR gamma with functional PPAR gamma-binding sites in its promoter.
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