Gene expression regulation by retinoic acid

Abstract

Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall. We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0). -Balmer, J. E., and R. Blomhoff BackgroundBeginning in at least the late 1960s, there was tremendous interest in whether the differentiating and tumor suppressing activities of retinoids reflected a genetic mechanism, on analogy to the steroid hormones, or an epigenetic one. It had been known for some time that retinoids could influence mRNA levels in certain cells, but also that they could increase activity on membrane-bound ribosomes. Any number of different mechanisms were possible, and quite a few were proposed. In a particularly

Effects of acute exposure to polybrominated diphenyl ethers on retinoid signaling in zebrafish larvae

“…RA can modulate gene transcription required for eye morphogenesis by binding and activating RARs and RXRs nuclear receptors (Novák et al, 2008). There is solid evidence showing that rhodopsin gene expression is regulated by RA (Balmer and Blomhoff, 2002). Various animal and cell culture models have also indicated an important role for RA in regulating the development of retina photoreceptors.…”

Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

“…In response to RA binding, RAR/RXR heterodimers regulate the transcription of a number of target genes by binding to the specific DNA response elements (Balmer and Blomhoff, 2002). Retinoic acids have antitumor effects on neuroblastoma-derived cell lines accompanied by a marked decrease in the expression levels of MYCN (Thiele et al, 1985).…”

Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma

“…In others, the control is indirect, reflecting the actions of intermediate transcription factors, nonclassical associations of receptors with other proteins or even more distant mechanisms. 9 Among a number of RA target genes in various systems, tazarotene-induced gene 1 (TIG1) and tazarotene-induced gene 3 (TIG3) were identified in skin and found as tumor suppressor genes in human cancers. 10 -12 TIG1 is a candidate tumor suppressor gene of human prostate cancer.…”