RRC ID 38350
Author Mullany LK, Hanse EA, Romano A, Blomquist CH, Mason JI, Delvoux B, Anttila C, Albrecht JH.
Title Cyclin D1 regulates hepatic estrogen and androgen metabolism.
Journal Am. J. Physiol. Gastrointest. Liver Physiol.
Abstract Cyclin D1 is a cell cycle control protein that plays an important role in regenerating liver and many types of cancer. Previous reports have shown that cyclin D1 can directly enhance estrogen receptor activity and inhibit androgen receptor activity in a ligand-independent manner and thus may play an important role in hormone-responsive malignancies. In this study, we examine a distinct mechanism by which cyclin D1 regulates sex steroid signaling, via altered metabolism of these hormones at the tissue and cellular level. In male mouse liver, ectopic expression of cyclin D1 regulated genes involved in the synthesis and degradation of sex steroid hormones in a pattern that would predict increased estrogen and decreased androgen levels. Indeed, hepatic expression of cyclin D1 led to increased serum estradiol levels, increased estrogen-responsive gene expression, and decreased androgen-responsive gene expression. Cyclin D1 also regulated the activity of several key enzymatic reactions in the liver, including increased oxidation of testosterone to androstenedione and decreased conversion of estradiol to estrone. Similar findings were seen in the setting of physiological cyclin D1 expression in regenerating liver. Knockdown of cyclin D1 in HuH7 cells produced reciprocal changes in steroid metabolism genes compared with cyclin D1 overexpression in mouse liver. In conclusion, these studies establish a novel link between the cell cycle machinery and sex steroid metabolism and provide a distinct mechanism by which cyclin D1 may regulate hormone signaling. Furthermore, these results suggest that increased cyclin D1 expression, which occurs in liver regeneration and liver diseases, may contribute to the feminization seen in these settings.
Volume 298(6)
Pages G884-95
Published 2010-6
DOI 10.1152/ajpgi.00471.2009
PII ajpgi.00471.2009
PMID 20338923
PMC PMC2907223
MeSH Androgens / biosynthesis* Animals Aromatase Inhibitors / pharmacology Cell Line, Tumor Cyclin D1 / genetics Cyclin D1 / metabolism* Estrogens / biosynthesis* Gene Expression Profiling Gene Expression Regulation / drug effects Gene Expression Regulation / physiology Humans Letrozole Liver / metabolism* Liver Regeneration Male Mice Mice, Inbred BALB C Nitriles / pharmacology Triazoles / pharmacology
IF 3.729
Times Cited 9
Human and Animal Cells