HORMONAL REGULATION OF ANDROGEN RECEPTOR EXPRESSION

Project: Research project

Description

The long term objectives of the proposed research are to understand the
effects of endocrine status on androgen receptor abundance in normal and
diseased target tissues and to evaluate the physiologic significance of
fluctuations in receptor number. In particular, the molecular mechanisms
involved in androgen-mediated regulation of androgen receptor mRNA and
protein levels will be investigated in cells expressing the androgen
receptor cDNA. The capacity of receptors to be regulated by cognate
ligand (autoregulation) is a feature common to virtually all members of
the steroid/thyroid hormone receptor family. In many target tissues and
androgen receptor-containing cell lines androgen treatment causes a
reduction in receptor mRNA and protein. Preliminary results suggest that
the expression of the human androgen receptor cDNA in transfected cells
is also down-regulated by androgen. Since the heterologous promoter used
to express the androgen receptor cDNA is insensitive to androgens,
sequences within the receptor cDNA must be responsible for autoregulation
of transfected androgen receptor mRNA. Experiments proposed here will
test the hypothesis that androgen-mediated regulation of androgen
receptor levels is achieved through the direct interaction of the
androgen receptor with sequences within the receptor cDNA or mRNA. The
specific aims of this proposal are: I. To evaluate the effects of
androgens on steady state levels, transcription and stability of androgen
receptor mRNA in cells transfected with the human androgen receptor cDNA.
II. TO evaluate the effects of androgens on steady state levels and
half-life of androgen receptor protein. III. To identify the intragenic
down regulatory signals of the androgen receptor cDNA by (A) mapping
androgen receptor binding to specific sequences within the androgen
receptor cDNA (or mRNA); (B) in vitro mutagenesis (site directed or
deletion) of receptor binding sites to ascertain the potential role of
these sequences in down regulation. Since steroid receptor content has
proven to be useful in predicting cellular responsiveness to steroid
hormones, understanding how receptors are regulated is vital to the
development of rational endocrine therapies. For example, modulation of
androgen levels is a central component in the clinical management of
prostate cancer. How cellular endocrine status affects androgen
receptors should aid oncologists in arriving at more effective strategies
for treatment of androgen-dependent tumors. Studies on steroid receptor
down regulation will provide insight into mechanisms that attenuate
cellular response to hormonal stimulation and that may be involved in the
clinical problem of steroid-resistant neoplasia.
StatusFinished
Effective start/end date9/30/928/31/05

Funding

  • National Institutes of Health: $99,109.00
  • National Institutes of Health: $161,204.00
  • National Institutes of Health: $52,557.00
  • National Institutes of Health: $104,736.00
  • National Institutes of Health
  • National Institutes of Health: $197,787.00
  • National Institutes of Health
  • National Institutes of Health: $192,026.00
  • National Institutes of Health
  • National Institutes of Health: $188,566.00
  • National Institutes of Health: $110,778.00
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Androgen Receptors
Androgens
Complementary DNA
Messenger RNA
Steroids
Up-Regulation
Homeostasis
Steroid Receptors
Thyroid Hormone Receptors
Neoplasms
Down-Regulation
Glucocorticoid Receptors
Site-Directed Mutagenesis
Proteins
RNA Stability
Genes
Exons

ASJC

  • Medicine(all)