A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR

doi:10.1016/0092-8674(81)90018-0

Cell

Volume 66, Issue 3, 9 August 1991, Pages 555-561

https://doi.org/10.1016/0092-8674(81)90018-0 Get rights and content

Abstract

The vitamin A derivative retinoic acid exerts its effects on transcription through two distinct classes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). We provide evidence that expression of the gene for cellular retinol-binding protein type II (CRBPII), a key protein in the intestinal absorption of vitamin A, is dramatically up-regulated by retinoic acid in the presence of RXR but not RAR. This regulation is conferred through a specific cis element in the CRBPII promoter that contains five nearly perfect tandem repeats of the sequence AGGTCA spaced by a single nucleotide. The discovery of this new RX response element provides a means for distinguishing between the two retinoid receptor systems and suggests that an RXR-mediated pathway exists for modulating vitamin A metabolism.

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Vitamin A is an important micro-essential nutrient, whose primary dietary source is retinyl esters. In addition, β-carotene (pro-vitamin A) is a precursor of vitamin A contained in green and yellow vegetables that is converted to retinol in the body after ingestion. Retinol is oxidized to produce visual retinal, which is further oxidized to retinoic acid (RA), which is used as a therapeutic agent for patients with promyelocytic leukemia. Thus, the effects of retinal and RA are well known. In this paper, we will introduce (1) vitamin A circulation in the body, (2) the actions and mechanisms of retinal and RA, (3) retinoylation: another RA mechanism not depending on RA receptors, (4) the relationship between cancer and actions of retinol or β-carotene, whose roles in vivo are still unknown, and (5) anti-cancer actions of vitamin A derivatives derived from fenretinide (4-HPR). We propose that vitamin A nutritional management is effective in the prevention of cancer.
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Genome expansion is believed to be an important driver of the evolution of gene regulation. To investigate the role of a newly arising sequence in rewiring regulatory networks, we estimated the age of each region of the human genome by applying maximum parsimony to genome-wide alignments with 100 vertebrates. We then studied the age distribution of several types of functional regions, with a focus on regulatory elements. The age distribution of regulatory elements reveals the extensive use of newly formed genomic sequence in the evolution of regulatory interactions. Many transcription factors have expanded their repertoire of targets through waves of genomic expansions that can be traced to specific evolutionary times. Repeated elements contributed a major part of such expansion: many classes of such elements are enriched in binding sites of one or a few specific transcription factors, whose binding sites are localized in specific portions of the element and characterized by distinctive motif words. These features suggest that the binding sites were available as soon as the new sequence entered the genome, rather than being created later by accumulation of point mutations. By comparing the age of regulatory regions to the evolutionary shift in expression of nearby genes, we show that rewiring through genome expansion played an important role in shaping human regulatory networks.

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Abstract

References (28)

Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development

Neuron

Transport and storage of vitamin A

Science

The cellular retinol binding protein II gene

J. Biol. Chem.

Identification of a retinoic acid responsive element in the retinoic acid receptor β gene

Nature

Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis

Mol. Cell. Biol.

The steroid and thyroid hormone receptor superfamily

Science

Identification of a receptor for the morphogen retinoic acid

Nature

Molecular cloning of cDNA encoding a second cellular retinoic acid-binding protein

The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements

Cell

Nuclear receptors enhance our understanding of transcription regulation

Trends Genet

Cyclic AMP analogs and retinoic acid influence the expression of retinoic acid receptor α, β, and λ mRNAs in F9 teratocarcinoma cells

Mol. Cell. Biol.

A functional retinoic acid receptor encoded by the gene on human chromosome 12

Mol. Endo.

Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D₃

CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements

Nucl. Acids Res.

Cited by (594)

Genome-wide perspectives on vitamin D receptor actions

Vitamin A in health care: Suppression of growth and induction of differentiation in cancer cells by vitamin A and its derivatives and their mechanisms of action

Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities

Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair

3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity

Evolutionary Rewiring of Human Regulatory Networks by Waves of Genome Expansion

Cell

ArticleA direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR

Abstract

Cloning of a novel glutamate receptor subunit, GluR5: expression in the nervous system during development

Neuron

Transport and storage of vitamin A

Science

The cellular retinol binding protein II gene

J. Biol. Chem.

Identification of a retinoic acid responsive element in the retinoic acid receptor β gene

Nature

Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis

Mol. Cell. Biol.

The steroid and thyroid hormone receptor superfamily

Science

Identification of a receptor for the morphogen retinoic acid

Nature

Molecular cloning of cDNA encoding a second cellular retinoic acid-binding protein

The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements

Cell

Nuclear receptors enhance our understanding of transcription regulation

Trends Genet

Cyclic AMP analogs and retinoic acid influence the expression of retinoic acid receptor α, β, and λ mRNAs in F9 teratocarcinoma cells

Mol. Cell. Biol.

A functional retinoic acid receptor encoded by the gene on human chromosome 12

Mol. Endo.

Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3

CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements

Nucl. Acids Res.

Article
A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR

Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D₃