THE NUCLEAR RECEPTOR FOR MELATONIN REPRESSES 5-LIPOXYGENASE GENE-EXPRESSION IN HUMAN B-LYMPHOCYTES

被引:242
作者
STEINHILBER, D
BRUNGS, M
WERZ, O
WIESENBERG, I
DANIELSSON, C
KAHLEN, JP
NAYERI, S
SCHRADER, M
CARLBERG, C
机构
[1] UNIV GENEVA,HOP CANTONAL,DERMATOL CLIN,CH-1211 GENEVA 14,SWITZERLAND
[2] UNIV TUBINGEN,INST PHARMAZEUT,D-72076 TUBINGEN,GERMANY
[3] CIBA GEIGY AG,PHARM FORSCH,CH-4002 BASEL,SWITZERLAND
关键词
D O I
10.1074/jbc.270.13.7037
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The two subtypes of retinoid Z receptor (RZR alpha and beta) and the three splicing variants of retinoid orphan receptor (ROR alpha 1, alpha 2, and alpha 3) form a subfamily within the superfamily of nuclear hormone receptors, Very recently we found that the pineal gland hormone melatonin is a natural ligand of RZR alpha and RZR beta. Ligand-induced transcriptional control is therefore proposed to mediate physiological functions of melatonin in the brain where RZR beta is expressed, but also in peripheral tissues, where RZR alpha was found. However, no natural RZR responding genes have been identified yet. Here, we report that a response element in the promoter of 5-lipoxygenase binds specifically RZR alpha and ROR alpha 1, but not ROR alpha 2 and alpha 3. 5-Lipoxygenase is a key enzyme in the biosynthesis of leukotrienes, which are known to be allergic and inflammatory mediators. We could show that the activity of the whole 5-lipoxygenase promoter as well as of the RZR response element fused to the heterologous thymidine kinase promoter could be repressed by melatonin. The hormone down-regulated the expression of 5-lipoxygenase about 5-fold in B lymphocytes, which express RZR alpha, In contrast, 5-lipoxygenase mRNA levels were not affected in differentiated monocytic and granulocytic cell lines, which do not express RZR alpha. This indicates that 5-lipoxygenase is the first natural RZR alpha responding gene. Furthermore, our results open up a new perspective in understanding the involvement of melatonin in inflammatory and immunological reactions.
引用
收藏
页码:7037 / 7040
页数:4
相关论文
共 36 条
[1]   IDENTIFICATION OF NUCLEAR RECEPTOR MESSENGER-RNAS BY RT-PCR AMPLIFICATION OF CONSERVED ZINC-FINGER MOTIF SEQUENCES [J].
BECKERANDRE, M ;
ANDRE, E ;
DELAMARTER, JF .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1993, 194 (03) :1371-1379
[2]  
BECKERANDRE M, 1994, J BIOL CHEM, V269, P28531
[3]  
BROCK TG, 1994, J BIOL CHEM, V269, P22059
[4]  
BRUNGS M, 1994, P NATL ACAD SCI USA, V92, P107
[5]   RZRS, A NEW FAMILY OF RETINOID-RELATED ORPHAN RECEPTORS THAT FUNCTION AS BOTH MONOMERS HOMODIMERS [J].
CARLBERG, C ;
VANHUIJSDUIJNEN, RH ;
STAPLE, JK ;
DELAMARTER, JF ;
BECKERANDRE, M .
MOLECULAR ENDOCRINOLOGY, 1994, 8 (06) :757-770
[6]   2 NUCLEAR SIGNALING PATHWAYS FOR VITAMIN-D [J].
CARLBERG, C ;
BENDIK, I ;
WYSS, A ;
MEIER, E ;
STURZENBECKER, LJ ;
GRIPPO, JF ;
HUNZIKER, W .
NATURE, 1993, 361 (6413) :657-660
[7]   EFFECTS OF MELATONIN ON THE CELL-CYCLE KINETICS AND ESTROGEN-RESCUE OF MCF-7 HUMAN BREAST-CANCER CELLS IN CULTURE [J].
COS, S ;
BLASK, DE ;
LEMUSWILSON, A ;
HILL, AB .
JOURNAL OF PINEAL RESEARCH, 1991, 10 (01) :36-42
[8]   CLONING OF THE CDNA FOR HUMAN 5-LIPOXYGENASE [J].
DIXON, RAF ;
JONES, RE ;
DIEHL, RE ;
BENNETT, CD ;
KARGMAN, S ;
ROUZER, CA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (02) :416-420
[9]   EXPRESSION CLONING OF A HIGH-AFFINITY MELATONIN RECEPTOR FROM XENOPUS DERMAL MELANOPHORES [J].
EBISAWA, T ;
KARNE, S ;
LERNER, MR ;
REPPERT, SM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (13) :6133-6137
[10]   THE STEROID AND THYROID-HORMONE RECEPTOR SUPERFAMILY [J].
EVANS, RM .
SCIENCE, 1988, 240 (4854) :889-895