PMID- 11245924
OWN - NLM
STAT- MEDLINE
DCOM- 20010628
LR  - 20190826
IS  - 0169-328X (Print)
IS  - 0169-328X (Linking)
VI  - 87
IP  - 2
DP  - 2001 Mar 5
TI  - 9-cis-Retinoic acid represses transcription of the gonadotropin-releasing hormone 
      (GnRH) gene via proximal promoter region that is distinct from all-trans-retinoic 
      acid response element.
PG  - 214-22
AB  - We previously reported an enhancing effect of all-trans-retinoic acid 
      (all-trans-RA) on gonadotropin-releasing hormone (GnRH) gene transcription via 
      distal promoter elements of the rat GnRH gene. The present study examined the 
      effects of another biologically active retinoid, 9-cis-retinoic acid (9-cis-RA), 
      on GnRH transcription in GT1-1 cells. Similar to the action of all-trans-RA, 
      9-cis-RA significantly induced the luciferase activity of the strong retinoic 
      acid response element (RARE) reporter construct, 3X beta RARE-Luc, by about 
      60-fold, indicating that GT1-1 cells are also responsive to 9-cis-RA. In contrast 
      to the stimulatory effect of all-trans-RA on GnRH transcription, 9-cis-RA 
      inhibited the GnRH promoter activity in a dose- and time-dependent manner. 
      Significant inhibition by 9-cis-RA required at least an 18 h treatment and a 
      further decrease of GnRH promoter-driven luciferase activity was observed up to 
      48 h of incubation. Accordingly, GnRH mRNA levels were decreased by 9-cis-RA 
      treatment in a similar dose- and time-related manner, indicating that mouse GnRH 
      expression is also negatively regulated by 9-cis-RA. Transient transfections of 
      serial deletion constructs of the rat GnRH promoter revealed that the --230/--110 
      sequence of the rat GnRH promoter is responsible for 9-cis-RA-induced inhibition 
      of GnRH transcription. Within this region, however, no consensus retinoid X 
      receptor response element was found. To gain insights into the role of retinoid X 
      receptors (RXRs) in GnRH expression, we examined the effects of RXR 
      overexpression on GnRH transcriptional activity. Interestingly, co-transfection 
      of RXR overexpression vectors significantly increased the GnRH promoter-driven 
      luciferase activity, while treatment with 9-cis-RA not only nullified the 
      enhancing effect of RXR overexpression but also decreased the basal GnRH 
      promoter-driven luciferase activity by 50% compared to vehicle-treated controls. 
      This implies that RXRs in the absence of its cognate ligand 9-cis-RA contribute 
      to the maintenance of basal GnRH gene transcription. Northern blot analysis 
      revealed that 9-cis-RA, but not all-trans-RA, down-regulated RXR beta expression 
      in GT1-1 cells, suggesting that one possible mechanism of 9-cis-RA-induced 
      repression involves down-regulation of RXR expression. In conclusion, the present 
      study clearly demonstrates that 9-cis-RA is a negative regulator of GnRH gene 
      expression in immortalized GnRH neurons.
FAU - Cho, S
AU  - Cho S
AD  - School of Biological Sciences and Research Center for Cell Differentiation, Seoul 
      National University, Seoul, 151-742, South Korea.
FAU - Chung, J
AU  - Chung J
FAU - Han, J
AU  - Han J
FAU - Ju Lee, B
AU  - Ju Lee B
FAU - Han Kim, D
AU  - Han Kim D
FAU - Rhee, K
AU  - Rhee K
FAU - Kim, K
AU  - Kim K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Brain Res Mol Brain Res
JT  - Brain research. Molecular brain research
JID - 8908640
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Ligands)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 33515-09-2 (Gonadotropin-Releasing Hormone)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Alitretinoin
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression Regulation/drug effects/physiology
MH  - Gonadotropin-Releasing Hormone/*genetics/metabolism
MH  - Ligands
MH  - Promoter Regions, Genetic/*genetics
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Receptors, Retinoic Acid/metabolism
MH  - Retinoid X Receptors
MH  - Transcription Factors/metabolism
MH  - Transcription, Genetic/drug effects/physiology
MH  - Transfection
MH  - Tretinoin/*pharmacology
EDAT- 2001/03/14 10:00
MHDA- 2001/06/29 10:01
CRDT- 2001/03/14 10:00
PHST- 2001/03/14 10:00 [pubmed]
PHST- 2001/06/29 10:01 [medline]
PHST- 2001/03/14 10:00 [entrez]
AID - S0169328X01000201 [pii]
AID - 10.1016/s0169-328x(01)00020-1 [doi]
PST - ppublish
SO  - Brain Res Mol Brain Res. 2001 Mar 5;87(2):214-22. doi: 
      10.1016/s0169-328x(01)00020-1.