Activation of the GDNF-inducible transcription factor (GIF) gene promoter by glucocorticoid and progesterone.
Steroid hormones, especially glucocorticoids, exert physiologic effects on dopaminergic neurotransmission and have been implicated in several dopamine-mediated neuropsychiatric conditions. D(2) dopamine receptor gene expression is regulated by the zinc finger-type nuclear protein GDNF-inducible transcription factor (GIF). In this study, we sought to investigate if steroids could regulate transcription of the GIF gene itself. Transient co-transfection of the D(2) expressing neuroblastoma cell line NB41A3 with GIF promoter-luciferase constructs along with expression vectors for steroid hormone receptors showed that activation of glucocorticoid receptors but not estrogen receptors up-regulates transcription from the GIF promoter 5.0-fold. Progesterone receptors, which share the same consensus DNA recognition sequence as glucocorticoid receptors, also activated the GIF promoter. Serial 5'-deletion mutants of the GIF gene upstream region localized the glucocorticoid-responsive segment between nucleotides -128 and -66 relative to the transcription start site. This region contains a putative glucocorticoid-responsive element/progesterone-responsive element (GRE/PRE). Additionally, this fragment of the GIF gene 5'-upstream region activated the heterologous herpes simplex virus thymidine kinase (TK) promoter, which is known to be glucocorticoid and progesterone responsive. Furthermore, glucocorticoid receptor activation up-regulated endogenous GIF gene mRNA expression in NB41A3 cells. These observations demonstrate a molecular basis for glucocorticoid and progesterone-induced up-regulation of GIF gene transcription and provide a mechanism for the modulation of dopamine-mediated behaviors by these hormones.
Lee
Sang-Hyeon
SH
Department of Bioscience and Biotechnology, Silla University, Gwaebop-dong, Sasang-Gu, Busan, Republic of Korea.
Jang
Min-Kyung
MK
Kim
Ok-Soo
OS
Lee
Ok-Hee
OH
Kim
Nam Young
NY
Yoo
Ki-Hwan
KH
Lee
Dong-Geun
DG
Shong
Young Hwa
YH
Mouradian
M Maral
MM
D000818:Animals; D045744:Cell Line, Tumor; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D011374:Progesterone / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D020218:Response Elements; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
C480234:GZF1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005938:Glucocorticoids; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011374:Progesterone