PMID- 8139538
OWN - NLM
STAT- MEDLINE
DCOM- 19940428
LR  - 20210526
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 14
IP  - 4
DP  - 1994 Apr
TI  - Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of 
      retinoic acid receptor alpha.
PG  - 2323-30
AB  - Retinoids exert their physiological action by interacting with two families of 
      nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X 
      receptors (RXRs), which regulate gene expression by forming transcriptionally 
      active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid 
      receptor activity resides in several regions, including the DNA and ligand 
      binding domains, a dimerization interface, and both a ligand-independent (AF-1) 
      and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid 
      (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA 
      (t-RA) compete for binding with high affinity to the RARs. This latter 
      observation suggested to us that the two isomers may interact with a common 
      binding site. Here we report that RAR alpha has two distinct but overlapping 
      binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino 
      acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but 
      truncation to amino acid 404 yields a mutant receptor that binds only t-RA with 
      high affinity. Remarkably, this region also defines a C-terminal boundary for 
      AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene 
      activity to a truncated human RAR alpha lacking this region. It is interesting to 
      speculate that binding of retinoid stereoisomers to unique sites within an RAR 
      may function with AF-2 to cause differential activation of retinoid-responsive 
      gene pathways.
FAU - Tate, B F
AU  - Tate BF
AD  - Department of Toxicology, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
FAU - Allenby, G
AU  - Allenby G
FAU - Janocha, R
AU  - Janocha R
FAU - Kazmer, S
AU  - Kazmer S
FAU - Speck, J
AU  - Speck J
FAU - Sturzenbecker, L J
AU  - Sturzenbecker LJ
FAU - Abarzua, P
AU  - Abarzua P
FAU - Levin, A A
AU  - Levin AA
FAU - Grippo, J F
AU  - Grippo JF
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (DNA, Complementary)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (RARA protein, human)
RN  - 0 (Rara protein, mouse)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Binding Sites
MH  - Cell Line
MH  - Cloning, Molecular
MH  - Consensus Sequence
MH  - DNA, Complementary/metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Macromolecular Substances
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutagenesis
MH  - Oligodeoxyribonucleotides
MH  - Protein Conformation
MH  - Receptors, Cytoplasmic and Nuclear/biosynthesis/genetics/metabolism
MH  - Receptors, Retinoic Acid/biosynthesis/genetics/*metabolism
MH  - Retinoic Acid Receptor alpha
MH  - Retinoid X Receptors
MH  - Sequence Deletion
MH  - Sequence Homology, Amino Acid
MH  - *Transcription Factors
MH  - Transcription, Genetic
MH  - Transfection
MH  - Tretinoin/*metabolism/pharmacology
PMC - PMC358599
EDAT- 1994/04/01 00:00
MHDA- 1994/04/01 00:01
PMCR- 1994/04/01
CRDT- 1994/04/01 00:00
PHST- 1994/04/01 00:00 [pubmed]
PHST- 1994/04/01 00:01 [medline]
PHST- 1994/04/01 00:00 [entrez]
PHST- 1994/04/01 00:00 [pmc-release]
AID - 10.1128/mcb.14.4.2323-2330.1994 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1994 Apr;14(4):2323-30. doi: 10.1128/mcb.14.4.2323-2330.1994.