PMID- 7852380
OWN - NLM
STAT- MEDLINE
DCOM- 19950315
LR  - 20210210
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 270
IP  - 7
DP  - 1995 Feb 17
TI  - Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers 
      are the major functional forms regulating retinoid-responsive elements in adult 
      human keratinocytes. Binding of ligands to RAR only is sufficient for RAR-RXR 
      heterodimers to confer ligand-dependent activation of hRAR beta 2/RARE (DR5).
PG  - 3001-11
AB  - We have examined how retinoic acid receptors (RARs) and retinoid X receptors 
      (RXRs) at physiological concentrations regulate distinct retinoid-responsive 
      elements, hRAR beta 2/beta RARE (DR5) and rCRBPII/RXRE (DR1), in keratinocytes 
      from human skin, a major retinoid target. In vitro, endogenous RAR gamma and RXRs 
      bound to these elements as heterodimers (RAR.RXR) but not homodimers (RAR.RAR or 
      RXR.RXR). In cultured keratinocytes, all-trans retinoic acid, 9-cis retinoic 
      acid, and CD367 activated beta RARE but not RXRE via endogenous RAR.RXR (ED50 = 
      2.3, 3.8, and 0.3 nM, respectively) whereas SR11237 showed no significant effect. 
      All-trans retinoic acid, 9-cis retinoic acid, and SR11237 activated RXRE via 
      overexpressed RXR.RXR (ED50 = 110, 120, and 11 nM, respectively), indicating 
      interconversion between retinoic acid isomers, whereas co-overexpression of RAR 
      alpha or RAR gamma suppressed this activation. Unlike 9cRA, CD367 neither induced 
      formation of nor activated RXR.RXR. Overexpression of RAR or RXR mutated in 
      transactivation domain AF-2 suppressed endogenous receptor activity over beta 
      RARE. Our data suggest that 1) in keratinocytes, RAR.RXR-mediated pathway 
      dominates over that mediated by RXR.RXR; 2) RAR-selective CD367 and RXR-selective 
      SR11237 can be used to identify these two distinct pathways, respectively; 3) 
      beta RARE is mainly regulated by RAR.RXR, in which RAR alone confers ligand 
      inducibility whereas AF-2 of unliganded RXR is required for transactivation by 
      liganded RAR AF-2; 4) lack of RXRE activity in keratinocytes is due to low 
      endogenous levels of RXR.RXR and inhibition by RAR.RXR; and 5) interaction among 
      RXRs is much lower than that between RAR and RXR.
FAU - Xiao, J H
AU  - Xiao JH
AD  - Department of Dermatology, University of Michigan, Ann Arbor 48109.
FAU - Durand, B
AU  - Durand B
FAU - Chambon, P
AU  - Chambon P
FAU - Voorhees, J J
AU  - Voorhees JJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Macromolecular Substances)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase)
RN  - EC 2.7.1.21 (Thymidine Kinase)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Base Sequence
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Chloramphenicol O-Acetyltransferase/biosynthesis
MH  - Gene Expression
MH  - Humans
MH  - Keratinocytes/cytology/drug effects/*metabolism
MH  - Macromolecular Substances
MH  - Molecular Sequence Data
MH  - Mutagenesis, Insertional
MH  - Oligodeoxyribonucleotides
MH  - Rats
MH  - Receptors, Retinoic Acid/biosynthesis/*metabolism
MH  - Recombinant Fusion Proteins/biosynthesis/*metabolism
MH  - Restriction Mapping
MH  - Retinoid X Receptors
MH  - Skin/cytology/*metabolism
MH  - Thymidine Kinase/biosynthesis
MH  - Transcription Factors/biosynthesis/*metabolism
MH  - Transcriptional Activation
MH  - Transfection
MH  - Tretinoin/*pharmacology
EDAT- 1995/02/17 00:00
MHDA- 1995/02/17 00:01
CRDT- 1995/02/17 00:00
PHST- 1995/02/17 00:00 [pubmed]
PHST- 1995/02/17 00:01 [medline]
PHST- 1995/02/17 00:00 [entrez]
AID - S0021-9258(18)82883-6 [pii]
AID - 10.1074/jbc.270.7.3001 [doi]
PST - ppublish
SO  - J Biol Chem. 1995 Feb 17;270(7):3001-11. doi: 10.1074/jbc.270.7.3001.