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Molecular and Cellular Biology, November 1998, p. 6482-6492, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Retinoic Acid Receptor gamma 1 (RARgamma 1) Levels Control RARbeta 2 Expression in SK-N-BE2(c) Neuroblastoma Cells and Regulate a Differentiation-Apoptosis Switch

Nicoletta Ferrari,1 Magnus Pfahl,2,3,* and Giovanni Levi1,4

Laboratorio di Biologia Molecolare, Istituto Nazionale per la Ricerca sul Cancro, c/o Centro di Biotecnologie Avanzate, Genoa, Italy1; Sidney Kimmel Cancer Center2 and MAXIA Pharmaceuticals,3 San Diego, California; and Laboratoire de Physiologie, Museum d'Histoire Naturelle, CNRS URA 90, Paris, France4

Received 3 February 1998/Returned for modification 30 April 1998/Accepted 15 July 1998

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

* Corresponding author. Mailing address: Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121. Phone: (619) 623-9632. Fax: (619) 824-1967.

Molecular and Cellular Biology, November 1998, p. 6482-6492, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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