Retinoic Acid Receptor γ1 (RARγ(1)) Levels Control RARβ(2) 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 RARγ(1) acts as a repressor of RARβ(2) transcription in the absence of an agonist. In the presence of RA, the expression of RARγ(1) is reduced and that of RARβ(2) is induced. Overexpression of RARγ(1) neutralizes the effects of RA on RARβ induction. Expression of an RARγ(1)-specific antisense construct leads to the constitutive expression of RARβ(2). Although both overexpression of RARγ(1) and its reduction of expression can result in inhibition of cell proliferation, they induce different morphological changes. Reduction of RARγ(1) (and induction of RARβ) leads to increased apoptosis, whereas RARγ(1) overexpression leads to differentiation in the absence of apoptosis. Thus, RARγ(1) appears to control a differentiation-apoptosis switch in SK-N-BE2(c) neuroblastoma cells.