The single-macro domain protein LRP16 is an essential cofactor of androgen receptor

Endocr Relat Cancer. 2009 Mar;16(1):139-53. doi: 10.1677/ERC-08-0150. Epub 2008 Nov 20.

Abstract

LRP16 is a special member of the macro domain superfamily, containing only a stand-alone macro domain functional module. Previous study demonstrated that the estrogenically regulated LRP16 cooperates with the estrogen receptor alpha and enhances the receptor's transcriptional activity in an estrogen-dependent manner. Here, we discovered that LRP16 binds to androgen receptor (AR) via its macro domain and amplifies the transactivation function of AR in response to androgen. Similarly, we also discovered that LRP16 acts as a potential coactivator to amplify the transactivation of at least other four nuclear receptors (NRs). Importantly, we show that the single macro domain in LRP16 can serve as the AR coactivator. RNA interference knockdown of LRP16 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as ART-27 and steroid receptor coactivator-1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. However, LRP16 knockdown did not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells. Furthermore, we observed the induction effect of LRP16 expression by androgen and established a feedforward mechanism that activated AR transactivation. Our results suggest that the macro domain protein LRP16 represents a novel type of cofactor of NR. They also indicate that LRP16 plays an essential role in AR transactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carboxylic Ester Hydrolases
  • Cell Cycle Proteins
  • Cell Division / physiology
  • Cell Line, Tumor
  • Cell-Free System
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone Acetyltransferases / metabolism
  • Humans
  • Ligands
  • Luciferases / genetics
  • Male
  • Molecular Chaperones
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism*
  • Nuclear Receptor Coactivator 1
  • Promoter Regions, Genetic / physiology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Structure, Tertiary
  • RNA, Small Interfering
  • Receptors, Androgen / metabolism*
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Up-Regulation / physiology

Substances

  • Cell Cycle Proteins
  • Ligands
  • Molecular Chaperones
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Receptors, Androgen
  • Transcription Factors
  • UXT protein, human
  • Luciferases
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • Carboxylic Ester Hydrolases
  • MACROD1 protein, human