Retinoic Acid Receptor g1 (RARg1) Levels Control RARb2 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 RARg1 acts as a repressor of RARb2 transcription in the absence of an agonist. In the presence of RA, the expression of RARg1 is reduced and that of RARb2 is induced. Overexpression of RARg1 neutralizes the effects of RA on RARb induction. Expression of an RARg1-specific antisense construct leads to the constitutive expression of RARb2. Although both overexpression of RARg1 and its reduction of expression can result in inhibition of cell proliferation, they induce different morphological changes. Reduction of RARg1 (and induction of RARb) leads to increased apoptosis, whereas RARg1 overexpression leads to differentiation in the absence of apoptosis. Thus, RARg1 appears to control a differentiation-apoptosis switch in SK-N-BE2(c) neuroblastoma cells.