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RAR‐specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage‐independent cell proliferation.
Author(s) -
Chen J.Y.,
Penco S.,
Ostrowski J.,
Balaguer P.,
Pons M.,
Starrett J.E.,
Reczek P.,
Chambon P.,
Gronemeyer H.
Publication year - 1995
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1995.tb07102.x
Subject(s) - biology , transactivation , microbiology and biotechnology , gene expression , gene , genetics
Using retinoic acid receptor (RAR) reporter cells specific for either RAR alpha, beta or gamma, we have identified synthetic retinoids which specifically induce transactivation by RAR beta, while antagonizing RA‐induced transactivation by RAR alpha and RAR gamma. Like RA, these synthetic retinoids allow all three RAR types to repress AP1 (c‐Jun/c‐Fos) activity, demonstrating that the transactivation and transrepression functions of RARs can be dissociated by properly designed ligands. Using AP1 reporter cells, we also show that glucocorticoids or vitamin D3, together with either RA or these ‘dissociating’ synthetic retinoids, can synergistically repress phorbol ester‐induced AP1 activity. RA, but not these ‘dissociating’ retinoids, induced transcription of an interleukin‐6 promoter‐based reporter gene transiently transfected into HeLa cells together with RARs. Using Ki‐ras‐transformed 3T3 cells as a model system, we show that both RA and the ‘dissociating’ retinoids inhibit anchorage‐independent cell proliferation, suggesting that retinoid‐induced growth inhibition may be related to AP1 transrepression.