OESTROGEN RECEPTORS



OESTROGEN RECEPTORS

•        Part of the steroid hormone super-family which includes the androgen receptor, progesterone and glucocorticoid receptor, aldosterone receptor, thyroid and retinoic acid receptor

•        Nuclear transcription factor with binding domains for DNA and oestrogens

•        Two sub-types - alpha and beta - the alpha sub-type has a half life of 4-7h.

•        Located in the nucleus even without ligand binding - the androgen, mineralocorticoid and glucocorticoid receptors on the other hand localise to the nucleus only after hormone binding

•        The oestrogen receptor, however, does undergo nucleocytoplasmic shuttling and is degraded in the cytoplasm

•        Have similar binding affinities for oestradiol but different tissue expression and distribution. Phytoestrogens, however, have a greater affinity for the beta receptor

•        Prior to ligand binding, the receptor is bound to a number of proteins including Heat Shock Protein 90 - dissociation of HSP 90 leads to activation of the receptor

•        Following oestradiol binding, the receptor dimerises and undergoes conformational changes with permit binding to oestrogen response elements which regulate the transcription of oestrogen-sensitive genes

•        Phosphorylation of the receptor and other peptides associated with it is an important mechanism of regulation - cAMP and protein kinase A pathways increase the transcriptional activity of the oestrogen receptor

•        Activated by growth factors such as epidermal growth factor, insulin-like growth factor-1 and TGF - alpha

•        Oestradiol, tamoxifen and raloxifene are agonists in bone; tamoxifen is an agonist in uterine tissue and tamoxifen and raloxifene are antagonists in breast

PROGESTERONE RECEPTOR

•        Expression is induced by oestrogen at the transcriptional level and inhibited by progesterone at the transcriptional and translational level

•        Two major forms - A & B

•        The inactive receptor is bound to heat shock protein 90

•        Progesterone binding leads to dimerisation with homodimers (AA) or heterodimers (AB)

•        The activated receptor binds DNA and regulates transcription of progesterone responsive genes

•        In most cell types, the B receptor is the positive regulator of progesterone sensitive genes

•        The A sub-type inhibits the activity of the B sub-type

ANDROGEN RECEPTOR

•        Exists as a full length B form and a shorter A form

•        Gene located on the X-chromosome - androgen insensitivity syndrome is an X-linked disorder

•        Similar to the progesterone, mineralocorticoid and glucocorticoid receptor - most similar to the progesterone receptor

•        Progestogens compete with androgens for the receptor and for the 5-alpha reductase system - dihydroprogesterone which is produced competes with testosterone and dihydrotestosterone

•        Has a greater affinity for dihydrotestosterone

•        Lower affinity for cyproterone acetate or spironolactone (~20%) compared to testosterone

Androgens produce biological effects by:

1) Direct actions of testosterone - endocrine effects

2) Intracellular conversion to dihydrotestosterone

3) Intracellular conversion of testosterone to oestradiol (aromatization)

•        Tissues derived from the Wollfian duct respond exclusively to testosterone

•        Hair follicles and derivatives of the urogenital sinus / tubercle require conversion to dihydrotestosterone by 5-alpha reductase

•        The hypothalamus actively converts androgens to oestrogens

 

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download