Retinoic acid receptor γ1 (RARγ1) levels control RARβ2 expression in SK-N-BE2(c) neuroblastoma cells and regulate a differentiation-apoptosis switch

Vitamin A and its derivatives (retinoids) have profound effects on the proliferation and differentiation of many cell types and are involved in a diverse array of developmental and physiological regulatory processes, including those responsible for the development of the mature nervous system. Retinoid signals are mediated by retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs), which show distinct spatio-temporal patterns of expression during development and in adult tissues. We have used SK-N-BE2(c) neuroblastoma cells to study the effects of reciprocal regulation of expression of various RARs. We show that in these cells RAR gamma(1) acts as a repressor of RAR beta(2) transcription in the absence of an agonist. In the presence of RA, the expression of RAR gamma(1) is reduced and that of RAR beta(2) is induced. Overexpression of RAR gamma(1) neutralizes the effects of RA on RAR beta induction. Expression of an RAR gamma(1)-specific antisense construct leads to the constitutive expression of RAR beta(2). Although both overexpression of RAR gamma(1) and its reduction of expression can result in inhibition of cell proliferation, they induce different morphological changes. Reduction of RAR gamma(1) (and induction of RAR beta) leads to increased apoptosis, whereas RAR gamma(1) overexpression leads to differentiation in the absence of apoptosis. Thus, RAR gamma(1) appears to control a differentiation-apoptosis switch in SK-N BE2(c) neuroblastoma cells.