PMID- 9187263
OWN - NLM
STAT- MEDLINE
DCOM- 19970714
LR  - 20231213
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 51
IP  - 6
DP  - 1997 Jun
TI  - Induction of apoptosis by retinoids and retinoic acid receptor gamma-selective 
      compounds in mouse thymocytes through a novel apoptosis pathway.
PG  - 972-82
AB  - Retinoic acids are morphogenic signaling molecules that are derived from vitamin 
      A and involved in a variety of tissue functions. Two groups of their nuclear 
      receptors have been identified: retinoic acid receptors (RARs) and retinoic acid 
      X receptors (RXRs). All-trans retinoic acid is the high affinity ligand for RARs, 
      and 9-cis retinoic acid also binds to RXRs with high affinity. In cells at high 
      concentrations, all-trans retinoic acid can be converted to 9-cis retinoic acid 
      via unknown mechanisms. It was previously shown that retinoic acids prevents 
      activation-induced death of thymocytes. Here, we report that both all-trans and 
      9-cis retinoic acid induce apoptosis of mouse thymocytes and purified CD4+CD8+ 
      cells in ex vivo cultures, with 9-cis retinoic acid being 50 times more 
      effective. The induction of apoptosis by retinoic acids is mediated by RARgamma 
      because (a) the phenomenon can be reproduced only by RARgamma-selective retinoic 
      acid analogs, (b) the cell death induced by either retinoic acids or RARgamma 
      analogs can be inhibited by RARgamma-specific antagonists, and (c) CD4+CD8+ 
      thymocytes express RARgamma. In vivo administration of an RARgamma analog 
      resulted in thymus involution with the concomitant activation of the 
      apoptosis-related endonuclease and induction of tissue transglutaminase. The 
      RARgamma pathway of apoptosis is RNA and protein synthesis dependent, affects the 
      CD4+CD8+ double positive thymocytes, and can be inhibited by the addition of 
      either Ca2+ chelators or protease inhibitors. Using various RAR- and RXR-specific 
      analogs and antagonists, it was demonstrated that stimulation of RAR alpha 
      inhibits the RARgamma-specific death pathway (which explains the lack of 
      apoptosis stimulatory effects of all-trans retinoic acid at physiological 
      concentrations) and that costimulation of the RXR receptors (in the case of 9-cis 
      retinoic acid) can neutralize this inhibitory effect. It is suggested that 
      formation of 9-cis retinoic acid may be a critical element in regulating both the 
      positive selection and the "default cell death pathway" of thymocytes.
FAU - Szondy, Z
AU  - Szondy Z
AD  - Department of Biochemistry, University Medical School of Debrecen, Hungary.
FAU - Reichert, U
AU  - Reichert U
FAU - Bernardon, J M
AU  - Bernardon JM
FAU - Michel, S
AU  - Michel S
FAU - Toth, R
AU  - Toth R
FAU - Ancian, P
AU  - Ancian P
FAU - Ajzner, E
AU  - Ajzner E
FAU - Fesus, L
AU  - Fesus L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (CD 437)
RN  - 0 (Rara protein, mouse)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Retinoids)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects/*physiology
MH  - CD4-Positive T-Lymphocytes/cytology/drug effects/ultrastructure
MH  - CD8-Positive T-Lymphocytes/cytology/drug effects/ultrastructure
MH  - Male
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Receptors, Retinoic Acid/*drug effects/*physiology
MH  - Retinoic Acid Receptor alpha
MH  - Retinoid X Receptors
MH  - Retinoids/*pharmacology
MH  - Thymus Gland/*cytology/*drug effects/ultrastructure
MH  - Transcription Factors/drug effects/physiology
MH  - Retinoic Acid Receptor gamma
EDAT- 1997/06/01 00:00
MHDA- 1997/06/01 00:01
CRDT- 1997/06/01 00:00
PHST- 1997/06/01 00:00 [pubmed]
PHST- 1997/06/01 00:01 [medline]
PHST- 1997/06/01 00:00 [entrez]
AID - 10.1124/mol.51.6.972 [doi]
PST - ppublish
SO  - Mol Pharmacol. 1997 Jun;51(6):972-82. doi: 10.1124/mol.51.6.972.