Role of E6-AP in the Development of Prostate Cancer

Project: Research project

Project Details

Description

DESCRIPTION (Provided by the applicant)
Androgens are important regulators of cell growth and prostate gland
development. Androgens exert their biological effects on target tissues through
an intracellular receptor protein named androgen receptor (AR). Recent evidence
suggests that transcriptional regulation by AR require a diverse group of
proteins termed coactivators. Coactivators portray a growing class of proteins
that interact with receptors in a hormone dependent manner and are required for
maximal gene activation by the receptors. It is the general belief that
coactivators enhance receptor function by acting as a bridge between the
DNA-bound receptor and basal transcription factors of the preinitiation complex
and also by providing histone acetyl transferase activity, HAT, which disrupts
the local repressive chromatin structure and contributes to increase
transcriptional activity. Recently, our laboratory has cloned, E6-associated
protein (E6-AP), as a coactivator of steroid receptors including that of AR.
E6-AP possesses ubiquitin-protein ligase activity, instead of HAT activity. Our
preliminary observation suggests that E6-AP act as a coactivator of AR and is
overexpressed both in mouse and human prostate tumors. The initial data from
E6-AP knockout mice also suggest that E6-AP play a major role in the normal
development of prostate gland. The prostate glands of the E6-AP knockout mice
are smaller and weigh less compare to that of wild-type normal littermates.
Furthermore, p53 levels are elevated in E6-AP knockout prostate glands.
Additionally, the AR expression is down in E6-AP knockout prostate. Based on
these initial findings, we hypothesize that E6-AP, an important modulator of
prostate gland, androgen receptor-mediated signal transduction pathway and cell
cycle control, is functionally significant in the development of normal
prostate gland and prostate cancer. In order to understand the exact role of
E6-AP in the development of normal prostate gland and in the development of
prostate tumors, we propose the following three specific aims: A) Development
and analysis of animal models for the overexpression of wild type E6-AP, C833S
mutant E6-AP (an E3 ubiquitin-protein ligase defective mutant) and loss of
E6-AP (E6-AP knockout) in the prostate gland, B), Design and development of
stable in vitro models for the overexpression of wild-type and C833S mutant
E6-AP proteins in the prostate cancer cell lines, and C) Expression analyses of
endogenous E6-AP, p53 and AR in prostate tumor biopsy samples.
StatusFinished
Effective start/end date9/30/018/31/06

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $201,750.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $12,000.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $64,394.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $225,750.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $158,789.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $213,750.00

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