Abstract
Jun dimerization protein 2 (JDP2), a basic leucine zipper transcription factor, is involved in numerous biological and cellular processes such as cancer development and regulation, cell-cycle regulation, skeletal muscle and osteoclast differentiation, progesterone receptor signaling, and antibacterial immunity. Though JDP2 is widely expressed in mammalian tissues, its function in gonads and adrenals (such as regulation of steroidogenesis and adrenal development) is largely unknown. Herein, we find that JDP2 mRNA and proteins are expressed in mouse adrenal gland tissues. Moreover, overexpression of JDP2 in Y1 mouse adrenocortical cancer cells increases the level of melanocortin 2 receptor (MC2R) protein. Notably, Mc2r promoter activity is activated by JDP2 in a dose-dependent manner. Next, by mapping the Mc2r promoter, we show that cAMP response elements (between −1320 and −720-bp) are mainly required for Mc2r activation by JDP2 and demonstrate that −830-bp is the major JDP2 binding site by real-time chromatin immunoprecipitation (ChIP) analysis. Mutations of cAMP response elements on Mc2r promoter disrupts JDP2 effect. Furthermore, we demonstrate that removal of phosphorylation of JDP2 results in attenuated transcriptional activity of Mc2r. Finally, we show that JDP2 is a candidate for SUMOylation and SUMOylation affects JDP2-mediated Mc2r transcriptional activity. Taken together, JDP2 acts as a novel transcriptional activator of the mouse Mc2r gene, suggesting that JDP2 may have physiological functions as a novel player in MC2R-mediated steroidogenesis as well as cell signaling in adrenal glands.
Highlights
Transcription factor activator protein 1 (AP-1) has been known to regulate gene expression in response to a variety of pathological and physiological stimuli, such as growth factors, infections, and stresses
Because Jun dimerization protein 2 (JDP2) has been shown to be phosphorylated at T148 by JNK (c-Jun N-terminal kinase) and p38 kinase [23], we examined the effect of phosphorylation of JDP2 on transcriptional activity of Mc2r promoter
While wild-type JDP2 significantly suppressed ATF3 promoter, 1-100 JDP2 mutant was not able to repress ATF3 promoter. We observed that both expression of T148A mutant protein and SUMO1-JDP2 fusion protein relieved the reduction by 20% and 10%, respectively. These results suggest that both phosphorylation and SUMOylation play a significant role in JDP2-mediated transcriptional activities
Summary
Transcription factor activator protein 1 (AP-1) has been known to regulate gene expression in response to a variety of pathological and physiological stimuli, such as growth factors, infections, and stresses. AP-1 plays an important role in controlling cellular processes including apoptosis, differentiation, and proliferation [1]. AP-1 is a heterodimeric protein and mainly consists of proteins belonging to the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. While c-Fos and c-Jun usually activate gene expression, Jun Dimerization protein 2 (JDP2) represses AP-1-mediated trans-activation by recruiting histone deacetylase 3 (HDAC3) to the promoter region [2,3]. In addition to AP-1 site, JDP2 binds to cAMP responsive element (CRE) site in numerous cis-elements of the target genes [4].
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