Aromatase Expression in Health and Disease

Evan R. Simpson, Ying Zhao, Veena R. Agarwal, M. Dodson Michael, Serdar E. Bulun, Margaret M. Hinshelwood, Sandra Graham-Lorence, Tiejun Sun, Carolyn R. Fisher, Kenan Qin, Carole R. Mendelson

Research output: Contribution to journalArticle

311 Citations (Scopus)

Abstract

Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the Δ4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNFa are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast rumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3′-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts - and hence the protein - are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5′-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration.

Original languageEnglish (US)
Pages (from-to)185-213
Number of pages29
JournalRecent Progress in Hormone Research
Volume52
StatePublished - 1997

Fingerprint

Aromatase
Estrogens
Health
Dinoprostone
Delayed Puberty
Interleukin-11
Genes
Virilism
Bone and Bones
Aromatase Inhibitors
Hypogonadism
Bone Development
Amenorrhea
Retinoids
Puberty
Cytochrome P-450 Enzyme System
Placenta
Androgens
Vertebrates
Adipose Tissue

ASJC Scopus subject areas

  • Endocrinology

Cite this

Simpson, E. R., Zhao, Y., Agarwal, V. R., Michael, M. D., Bulun, S. E., Hinshelwood, M. M., ... Mendelson, C. R. (1997). Aromatase Expression in Health and Disease. Recent Progress in Hormone Research, 52, 185-213.

Aromatase Expression in Health and Disease. / Simpson, Evan R.; Zhao, Ying; Agarwal, Veena R.; Michael, M. Dodson; Bulun, Serdar E.; Hinshelwood, Margaret M.; Graham-Lorence, Sandra; Sun, Tiejun; Fisher, Carolyn R.; Qin, Kenan; Mendelson, Carole R.

In: Recent Progress in Hormone Research, Vol. 52, 1997, p. 185-213.

Research output: Contribution to journalArticle

Simpson, ER, Zhao, Y, Agarwal, VR, Michael, MD, Bulun, SE, Hinshelwood, MM, Graham-Lorence, S, Sun, T, Fisher, CR, Qin, K & Mendelson, CR 1997, 'Aromatase Expression in Health and Disease', Recent Progress in Hormone Research, vol. 52, pp. 185-213.
Simpson ER, Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood MM et al. Aromatase Expression in Health and Disease. Recent Progress in Hormone Research. 1997;52:185-213.
Simpson, Evan R. ; Zhao, Ying ; Agarwal, Veena R. ; Michael, M. Dodson ; Bulun, Serdar E. ; Hinshelwood, Margaret M. ; Graham-Lorence, Sandra ; Sun, Tiejun ; Fisher, Carolyn R. ; Qin, Kenan ; Mendelson, Carole R. / Aromatase Expression in Health and Disease. In: Recent Progress in Hormone Research. 1997 ; Vol. 52. pp. 185-213.
@article{06daaaa386af4355be37627192ba363c,
title = "Aromatase Expression in Health and Disease",
abstract = "Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the Δ4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNFa are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast rumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3′-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts - and hence the protein - are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5′-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration.",
author = "Simpson, {Evan R.} and Ying Zhao and Agarwal, {Veena R.} and Michael, {M. Dodson} and Bulun, {Serdar E.} and Hinshelwood, {Margaret M.} and Sandra Graham-Lorence and Tiejun Sun and Fisher, {Carolyn R.} and Kenan Qin and Mendelson, {Carole R.}",
year = "1997",
language = "English (US)",
volume = "52",
pages = "185--213",
journal = "Recent Progress in Hormone Research",
issn = "0079-9963",
publisher = "The Endocrine Society",

}

TY - JOUR

T1 - Aromatase Expression in Health and Disease

AU - Simpson, Evan R.

AU - Zhao, Ying

AU - Agarwal, Veena R.

AU - Michael, M. Dodson

AU - Bulun, Serdar E.

AU - Hinshelwood, Margaret M.

AU - Graham-Lorence, Sandra

AU - Sun, Tiejun

AU - Fisher, Carolyn R.

AU - Qin, Kenan

AU - Mendelson, Carole R.

PY - 1997

Y1 - 1997

N2 - Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the Δ4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNFa are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast rumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3′-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts - and hence the protein - are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5′-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration.

AB - Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the Δ4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNFa are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast rumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3′-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts - and hence the protein - are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5′-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration.

UR - http://www.scopus.com/inward/record.url?scp=0030630195&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030630195&partnerID=8YFLogxK

M3 - Article

VL - 52

SP - 185

EP - 213

JO - Recent Progress in Hormone Research

JF - Recent Progress in Hormone Research

SN - 0079-9963

ER -