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Supplement

Introduction

Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907 1999.

	INTRODUCTION

TOP INTRODUCTION REFERENCES

 
This symposium was intended to introduce potential molecular mechanisms whereby nutrients modulate carcinogenesis via activation of one or more steroid hormone receptors. In particular, this symposium focused on several nutrients or nutritional behaviors (i.e., retinoic acids, vitamin D, certain polyunsaturated fatty acids and eicosanoid products, estrogen, and energy restriction) that are known to be chemoprotective and modulate gene expression. Therefore, the broad objective was to introduce the idea that many nutrients exert potent chemoprotective properties via activation of their respective nuclear receptors [i.e., the retinoic acid receptors, RAR and RXR; vitamin D receptors; peroxisome proliferator–activated receptors (PPAR); estrogen receptors; and glucocorticoid receptors]. The activation of each receptor class results in transcription of metabolic target genes that may modulate carcinogenesis.

Steroid hormone receptors (or "nuclear receptors") include a large superfamily of transcription factors that generally require a ligand for activation. As members of the nuclear receptor superfamily, each receptor contains five functional domains or regions (Fig. 1 ).The DNA binding region (C) contains two zinc finger motifs and is highly conserved among receptors. In contrast, the ligand binding domains (E and F) regulate heterodimerization and transcriptional activation and are less conserved across the isoforms within each class of receptor. Although activity of nuclear receptors is thought to be determined predominantly by ligand activation, there also exists a group of orphan receptors that have not yet been found to have specific, high affinity ligands for activation. Once activated either by ligand-dependent or ligand-independent means, homo- or heterodimerization of the nuclear receptor occurs for the majority of nuclear receptors within the F domain. The activated complex binds to specific consensus sequences (responsive elements) in the enhancer region of a number of genes, and transcriptional activation may occur if other transcription factors are present.

View larger version (6K): [in this window] [in a new window]   Figure 1. Molecular organization of functional domains of nuclear receptors. A/B, transcriptional activation domain; C, DNA binding domain; D, hinge region; E/F, ligand binding, dimerization and transcriptional activation domain. AF-1 includes A and B regions, AF-2.

View larger version (22K): [in this window] [in a new window]   Figure 2. Schematic diagram of interaction of several chemoprotective nutrients via activation of steroid hormone receptors. SHR, steroid hormone receptor.

Finally, although a large effort is being made to elucidate fully the mechanisms of action of nuclear receptors to modulate gene expression, an area that requires keen attention is the identification of novel genes that are mediated by these receptors and that are known to modulate carcinogenesis. In particular, genes associated with regulating cell growth, differentiation and/or apoptosis are the focus of a number of laboratories. For example, the gene, p21^Cip1/Waf1 is known to modulate cell cycle and has recently been found to contain a responsive element for the vitamin D receptor (Freedman 1999 ). These data offer promise that activation of vitamin D receptors may be directly linked to reduced proliferation and/or modulation of differentiation that results in the inhibition of cancer cell growth.

	FOOTNOTES

 
¹ Presented at the symposium "Steroid Hormone Receptor and Nutrient Interactions: Implications for Cancer Prevention" as part of Experimental Biology 98, April 18–22, 1998, San Francisco, CA. The symposium was sponsored by the American Society for Nutritional Sciences and was supported in part by educational grants from Loders Croklaan, Inc. and Slimfast Nutrition Institute. Published as a supplement to The Journal of Nutrition. Guest editors for the symposium publication were Diane F. Birt, Iowa State University and Martha Belury, Purdue University.

	REFERENCES

TOP INTRODUCTION REFERENCES

 

1. Birt D. F., Yatkine A., Duysen E.. Glucocorticoid mediation of dietary energy restriction inhibition of mouse skin carcinogenesis. J. Nutr. 1999;129:571S-574S.

2. Freedman L. P.. Trancriptional targets of the vitamin D-3 receptor–mediating cell cycle arrest and differentiation. J. Nutr. 1999;129:581S-586S.

3. Spady T. J., Harvell D.M.E., Lemus-Wilson A., Strecker T. E., Pennington K. L., Vander Woude E. A., Birt D. F., McComb R. D., Shull J. D.. Modulation of estrogen action in the rat pituitary and mammary glands by dietary energy consumption. J. Nutr. 1999;129:587S-590S.

4. Vanden Heuvel J. P.. Peroxisome proliferator–activated receptorsa critical link among fatty acids, gene expression and carcinogenesis. J. Nutr. 1999;129:575S-580S.

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