AROMATASE IN ADIPOSE--RELATIONSHIP TO AGING AND CANCER

脂肪中的芳香酶——与衰老和癌症的关系

• 批准号: 7073191
• 负责人: EVAN R SIMPSON
• 金额: $ 5.4万
• 依托单位: PRINCE HENRY'S INSTITUTE OF MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-06-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073191
• 关键词: DNA footprinting; RNA binding protein; RNA splicing; adipose tissue; aging; aromatase; breast neoplasms; cyclic AMP; estrogens; gel mobility shift assay; gene expression; genetic promoter element; genetic regulation; genetic regulatory element; glucocorticoids; growth factor; hormone related neoplasm /cancer; human genetic material tag; human tissue; laboratory rabbit; nucleic acid sequence; polymerase chain reaction; steroid hormone biosynthesis; tissue /cell culture; transcription factor

In the human, estrogens are synthesized in a number of tissue sites including ovarian granulosa cells and corpus luteum, placental syncytiotrophoblast, various sites in the brain, as well as adipose tissue. Estrogen biosynthesis in adipose tissue increases not only with obesity but also with age. Its physiological significance is unclear, but from a pathophysiological standpoint it has been implicated in a number of human diseases, notably endometrial cancer and breast cancer. In order to study the regulation of estrogen biosynthesis we have cloned and characterized the gene encoding human aromatase cytochrome P450 (P450arom), the enzyme responsible for estrogen biosynthesis. We have found that this gene exceeds 70 kb in length and that its tissue-specific expression is regulated by the use of alternative promoters. In the ovary expression is regulated by a promoter proximal to the translational start site (promoter II). In the placenta, expression is regulated by a promoter which is at least 40 kb upstream from the start of translation (promoter I.l). In adipose tissue in situ, expression is regulated by a third promoter (1.4) whose position within the gene has yet to be ascertained. Unexpectedly, when human adipose stromal cells are placed in culture, promoter selection appears to be dictated by the culture conditions, namely the presence or absence of cAMP, dexamethasone and growth factors. In order to study the molecular and cellular mechanisms responsible for this novel regulation of gene expression, we propose to characterize the regulatory elements present in regions of the gene upstream of each of the promoters which drive expression in adipose stromal cells, as well as in situ. The transcription factors which interact with these genomic regulatory elements will be characterized and their role in hormonal and tissue-specific regulation defined. In particular, we wish to determine the role of growth factors in switching promoter use in cells in culture. We will also seek to establish whether transcriptional activation or inhibition per se is sufficient to determine the switching of promoter use or whether additional mechanisms are required, such as the regulation of alternative splicing factors which determine the preferential employment of specific 5'-splice sites. Lastly, we will determine the relative importance of these various factors and mechanisms in the physiological regulation of estrogen biosynthesis in adipose tissue, for example, the increase which occurs as a function of aging, and the variation with regional fat distribution. In particular we will address the concept that breast tumor development is influenced by the regional distribution of estrogen biosynthesis in local areas of the breast, and the mechanisms whereby such gradients of P450arom expression are established and maintained will be investigated. We believe that these studies will provide new insights into the regulation of mammalian gene expression in general as well as of P450arom expression in particular, but especially will throw light on age-dependent processes involving estrogen biosynthesis in adipose tissue, namely the increase that occurs as a function of aging, as well as the implication of adipose tissue estrogen biosynthesis in the development of cancer.

在人体中，雌激素在许多组织部位合成

项目成果

Characterization of the sequences of the human CYP19 (aromatase) gene that mediate regulation by glucocorticoids in adipose stromal cells and fetal hepatocytes.

人类 CYP19（芳香酶）基因序列的表征，该基因介导脂肪基质细胞和胎儿肝细胞中糖皮质激素的调节。

• DOI: 10.1210/mend.9.3.7776980
• 发表时间: 1995
• 期刊: Molecular endocrinology (Baltimore, Md.)
• 作者: Zhao,Y;Mendelson,CR;Simpson,ER
• 通讯作者: Simpson,ER

Inverse relationship between ovarian aromatase cytochrome P450 and 5 alpha-reductase enzyme activities and mRNA levels during the estrous cycle in the rat.

大鼠动情周期中卵巢芳香酶细胞色素 P450 和 5α-还原酶活性与 mRNA 水平之间的负相关关系。

• DOI: 10.1016/0960-0760(92)90255-h
• 发表时间: 1992
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Lephart,ED;Doody,KJ;McPhaul,MJ;Simpson,ER
• 通讯作者: Simpson,ER

Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads.

使用组织特异性启动子调节人类睾丸和卵巢性索肿瘤以及正常胎儿和成人性腺中芳香酶细胞色素 P450 基因的表达。

• DOI: 10.1210/jcem.78.2.8106605
• 发表时间: 1994
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Bulun,SE;Rosenthal,IM;Brodie,AM;Inkster,SE;Zeller,WP;DiGeorge,AM;Frasier,SD;Kilgore,MW;Simpson,ER
• 通讯作者: Simpson,ER

Ligands for the peroxisomal proliferator-activated receptor gamma and the retinoid X receptor inhibit aromatase cytochrome P450 (CYP19) expression mediated by promoter II in human breast adipose.

过氧化物酶体增殖物激活受体 γ 和类视黄醇 X 受体的配体抑制人乳腺脂肪中由启动子 II 介导的芳香酶细胞色素 P450 (CYP19) 表达。

• DOI: 10.1210/endo.143.8.8932
• 发表时间: 2002
• 期刊: Endocrinology.
• 作者: Rubin,GaryL;Duong,JennyH;Clyne,ColinD;Speed,CarolineJ;Murata,Yoko;Gong,Changhong;Simpson,EvanR
• 通讯作者: Simpson,EvanR

Tissue-specific and hormonally controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue.

• DOI: 10.1016/s0021-9258(19)36538-x
• 发表时间: 1993-09
• 期刊: The Journal of biological chemistry
• 作者: M. Mahendroo;C. Mendelson;E. Simpson;E. Simpson