PMID- 8662628
OWN - NLM
STAT- MEDLINE
DCOM- 19960829
LR  - 20210210
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 271
IP  - 20
DP  - 1996 May 17
TI  - A novel class of retinoid antagonists and their mechanism of action.
PG  - 11897-903
AB  - Retinoids regulate a broad range of biological processes through two subfamilies 
      of nuclear retinoid receptors, the retinoic acid receptors (RARs) and the 
      retinoid X receptors (RXRs). Recently, we reported a novel type of retinoic acid 
      antagonist (SR11335) and showed that this compound can inhibit retinoic acid 
      (RA)-induced activation of a human immunodeficiency virus type 1 (HIV-1) promoter 
      construct that contains a special RA response element (RARE). We have now further 
      characterized the antagonism mediated by SR11335 and of newly synthesized 
      structurally related compounds. Two compounds, SR11330 and SR11334, which are 
      poor transactivators, also showed antagonist activities, inhibiting all-trans-RA 
      (tRA) and 9-cis-RA. The retinoids inhibited transcriptional activation of RAR/RXR 
      heterodimers effectively, while inhibition of RXR homodimers was less efficient. 
      Inhibition was observed on several RAREs, including the TREpal, betaRARE, 
      apoAI-RARE, and CRBPI-RARE. In addition, the antagonists inhibited tRA-induced 
      differentiation of HL-60 cells. The antagonist did not interfere with DNA binding 
      of the receptors. In limited proteolytic digestion assays, SR11335 induced 
      resistance of the receptors to proteolysis, but the pattern of the degradation 
      was not altered from that induced by tRA, suggesting that these antagonists 
      induce their biological effects by competing with agonists for binding to RARs, 
      thereby preventing the induction of conformational changes of the receptors 
      necessary for transcriptional activation.
FAU - Lee, M O
AU  - Lee MO
AD  - Sidney Kimmel Cancer Center, La Jolla, California 92037, USA.
FAU - Dawson, M I
AU  - Dawson MI
FAU - Picard, N
AU  - Picard N
FAU - Hobbs, P D
AU  - Hobbs PD
FAU - Pfahl, M
AU  - Pfahl M
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoids)
RN  - 0 (Trans-Activators)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Differentiation/drug effects
MH  - DNA/metabolism
MH  - HL-60 Cells
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Protein Conformation
MH  - Receptors, Retinoic Acid/antagonists & inhibitors
MH  - Retinoids/*antagonists & inhibitors/pharmacology
MH  - Structure-Activity Relationship
MH  - Trans-Activators/pharmacology
EDAT- 1996/05/17 00:00
MHDA- 1996/05/17 00:01
CRDT- 1996/05/17 00:00
PHST- 1996/05/17 00:00 [pubmed]
PHST- 1996/05/17 00:01 [medline]
PHST- 1996/05/17 00:00 [entrez]
AID - S0021-9258(18)82638-2 [pii]
AID - 10.1074/jbc.271.20.11897 [doi]
PST - ppublish
SO  - J Biol Chem. 1996 May 17;271(20):11897-903. doi: 10.1074/jbc.271.20.11897.