A decade of molecular biology of retinoic acid receptors

Abstract

Retinoids play an important role in development, differentiation, and homeostasis. The discovery of retinoid receptors belonging to the superfamily of nuclear ligand-activated transcriptional regulators has revolutionized our molecular understanding as to how these structurally simple molecules exert their pleiotropic effects. Diversity in the control of gene expression by retinoid signals is generated through complexity at different levels of the signaling pathway. A major source of diversity originates from the existence of two families of retinoid acid (RA) receptors (R), the RAR isotypes (alpha, beta, and gamma) and the three RXR isotypes (alpha, beta, and gamma), and their numerous isoforms, which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. The possibility of cross-modulation (cross-talk) with cell-surface receptors signaling pathways, as well as the finding that RARs and RXRs interact with multiple putative coactivators and/or corepressors, generates additional levels of complexity for the array of combinatorial effects that underlie the pleiotropic effects of retinoids. This review focuses on recent developments, particularly in the area of structure-function relationships.

Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells

“…By overexpressing RARa and phosphorylation-defective RARaS77A in parallel in either RARa mutant or RARaÀ/À cells, we along with others have found that RARaS77A, but not RARa, inhibits proliferation and induces differentiation in either normal or cancer cells (Taneja et al, 1997;Rochette-Egly et al, 2000;Crowe and Kim, 2002;Luo et al, 2007;Wang et al, 2009). RA-bound RARs and/or RXRs function as transcription factors to induce transactivation by modulating protein-DNA interactions at the RA responsive element (RARE) in the promoters of target genes (Mangelsdorf et al, 1991;Zhang et al, 1992;Chambon, 1996), although the underlying mechanisms remain to be dissected.…”

“…Numerous experiments and clinical trials have shown that RA and its derivatives are potent agents used for cancer therapy by inducing differentiation of acute myeloid leukemia and various other tumor cells, including breast, melanoma, neuroblastoma and squamous cell cancers (Beere and Hickman, 1993). Retinoids exert most of their effects by binding to nuclear RA receptors (RARs) and retinoid X receptors (RXRs), which are members of the steroid/thyroid hormone receptor superfamily (Evans, 1988;Chambon, 1996). RA is a biologically active ligand for these receptors, notably RARs (Evans, 1988;Chambon, 1996).…”

“…Retinoids exert most of their effects by binding to nuclear RA receptors (RARs) and retinoid X receptors (RXRs), which are members of the steroid/thyroid hormone receptor superfamily (Evans, 1988;Chambon, 1996). RA is a biologically active ligand for these receptors, notably RARs (Evans, 1988;Chambon, 1996). RARa has two major isoforms, RARa1 and RARa2 (Leroy et al, 1991;Chambon, 1996).…”

“…RA is a biologically active ligand for these receptors, notably RARs (Evans, 1988;Chambon, 1996). RARa has two major isoforms, RARa1 and RARa2 (Leroy et al, 1991;Chambon, 1996). RARa1 (referred as RARa below) is phosphorylated in its B region at serine 77 (S77) by the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex Bastien and Rochette-Egly, 2004).…”

“…RARa1 (referred as RARa below) is phosphorylated in its B region at serine 77 (S77) by the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex Bastien and Rochette-Egly, 2004). It is well known that functions of RARa are mediated through heterodimer interaction, protein degradation or phosphorylation regulation (Chambon, 1996;Bastien and Rochette-Egly, 2004). By overexpressing RARa and phosphorylation-defective RARaS77A in parallel in either RARa mutant or RARaÀ/À cells, we along with others have found that RARaS77A, but not RARa, inhibits proliferation and induces differentiation in either normal or cancer cells (Taneja et al, 1997;Rochette-Egly et al, 2000;Crowe and Kim, 2002;Luo et al, 2007;Wang et al, 2009).…”