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First published online on January 4, 2005
Endocrine Reviews, doi:10.1210/er.2002-0050
A more recent version of this article appeared on June 1, 2005
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*Genetics Home Reference

Molecular biology of the 3{beta}-hydroxysteroid dehydrogenase/{Delta}5-{Delta}4 isomerase gene family

Jacques Simard*, Marie-Louise Ricketts, Sébastien Gingras, Penny Soucy, F. Alex Feltus, and Michael H. Melner

Canada Research Chair in Oncogenetics, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), and Laval University, Quebec, Canada; Departments of Obstetrics/Gynecology and Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232 USA

* To whom correspondence should be addressed. E-mail: jacques.simard{at}crchul.ulaval.ca.

The 3{beta}-hydroxysteroid dehydrogenase/{Delta} (5)-{Delta} (4) isomerase (3{beta}-HSD) isoenzymes are responsible for the oxidation and isomerisation of {Delta} (5)-3{beta}-hydroxysteroid precursors into {Delta} (4)-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. In humans, expression of the type I isoenzyme accounts for the 3{beta}-HSD activity found in placenta and peripheral tissues, whereas the type II 3{beta}-HSD isoenzyme is predominantly expressed in the adrenal gland, ovary and testis and its deficiency is responsible for a rare form of congenital adrenal hyperplasia. Phylogeny analyses of the 3{beta}-HSD gene family strongly suggest that the need for different 3{beta}-HSD genes occurred very late in mammals, with subsequent evolution in a similar manner in other lineages. Therefore, to a large extent, the 3{beta}-HSD gene family should have evolved, to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids and cytokines. Recent studies indicate that HSD3B2 gene regulation involves the orphan nuclear receptors SF-1 and DAX-1. Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter. It was shown that EGF requires intact STAT5, on the other hand IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. However, evidence suggests that multiple signal transduction pathways are involved in IL-4 mediated HSD3B1 gene expression. Indeed, a better understanding of the transcriptional factors responsible of the fine control of 3{beta}-HSD gene expression may provide insight into mechanisms involved in the functional cooperation between STATs and nuclear receptors as well as their potential interaction with other signaling transduction pathways. Finally, the elucidation of the molecular basis of 3{beta}-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3{beta}-HSD deficiency and also provides valuable information concerning the structure-function relationships of the 3{beta}-HSD superfamily. Furthermore, several recent studies using type I and type II purified enzymes have elegantly further characterized structure-function relationships responsible for kinetic differences and coenzyme specificity.
Key words: steroidogenesis • congenital adrenal hyperplasia • pseudohermaphroditism • adrenal • ovary • testis • breast • prostate • liver • skin • transcription • STAT • interleukin-4 • prolactin • signal transduction pathways • structure-function relationships • rogens • estrogens • glucocorticoids • aldosterone




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