Cell-type and promoter-context dependent retinoic acid receptor (RAR) redundancies for RAR beta 2 and Hoxa-1 activation in F9 and P19 cells can be artefactually generated by gene knockouts.
By using RAR type (alpha, beta, or gamma)-specific synthetic retinoids and a pan-retinoic X receptor (RXR)-specific ligand, we have investigated the contribution of RARs and RXRs in the activation of RA target genes and the differentiation of embryonal carcinoma cells. We demonstrate cell-type- and promoter context-dependent functional redundancies that differ between the three RAR types for mediating the induction of RARbeta2 and Hoxa-1 in wild-type, RARgamma-/- and RARalpha-/- F9 cells and in P19 cells. The extent of redundancy between RARs is further modulated by the synergistic activation of RXRs with a pan-RXR agonist. We also demonstrate that the expression of RARbeta2 is auto-inducible in RARgamma-/- but not in wild-type F9 cells, indicating that the functional redundancies observed between RARs in gene disruption studies can be artefactually generated. Thus, even though all three RARs can functionally substitute each other for inducing the expression of RA target genes and cell differentiation, one RAR can cell-specifically override the activity of the other RARs. Interestingly, only RARgamma can mediate the retinoic acid-induced differentiation of wild-type F9 cells, whereas the differentiation of P19 cells can be mediated by either RARalpha or RARgamma.
Taneja
R
R
Institut de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, France.
Roy
B
B
Plassat
J L
JL
Zusi
C F
CF
Ostrowski
J
J
Reczek
P R
PR
Chambon
P
P
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D054278:Embryonal Carcinoma Stem Cells; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D014411:Neoplastic Stem Cells; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics*; D012176:Retinoids / Q000494:pharmacology
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids