Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein

J Biol Chem. 2003 Jun 13;278(24):22119-27. doi: 10.1074/jbc.M212822200. Epub 2003 Apr 7.

Abstract

PELP1 (proline-, glutamic acid-, and leucine-rich protein-1 (also referred to as MNAR, or modulator of nongenomic activity of estrogen receptor)), a recently identified novel coactivator of estrogen receptors, is widely expressed in a variety of 17 beta-estradiol (E2)-responsive reproductive tissues and is developmentally regulated in mammary glands. pRb (retinoblastoma protein), a cell cycle switch protein, plays a fundamental role in the proliferation, development, and differentiation of eukaryotic cells. To study the putative function of PELP1, we established stable MCF-7 breast cancer cell lines overexpressing PELP1. PELP1 overexpression hypersensitized breast cancer cells to E2 signaling, enhanced progression of breast cancer cells to S phase, and led to persistent hyperphosphorylation of pRb in an E2-dependent manner. Using phosphorylation site-specific pRb antibodies, we identified Ser-807/Ser-811 of pRb as a potential target site of PELP1. Interestingly, PELP1 was discovered to be physiologically associated with pRb and interacted via its C-terminal pocket domain, and PELP1/pRb interaction could be modulated by antiestrogen agents. Using mutant pRb cells, we demonstrated an essential role for PELP1/pRb interactions in the maximal coactivation functions of PELP1 using cyclin D1 as one of the targets. Taken together, these findings suggest that PELP1, a steroid coactivator, plays a permissive role in E2-mediated cell cycle progression, presumably via its regulatory interaction with the pRb pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Northern
  • Breast Neoplasms / metabolism
  • Cell Cycle
  • Co-Repressor Proteins
  • DNA, Complementary / metabolism
  • Disease Progression
  • Estrogens / metabolism
  • Glutathione Transferase / metabolism
  • Humans
  • Immunoblotting
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Retinoblastoma Protein / chemistry
  • Retinoblastoma Protein / metabolism*
  • S Phase
  • Time Factors
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • Co-Repressor Proteins
  • DNA, Complementary
  • Estrogens
  • PELP1 protein, human
  • Retinoblastoma Protein
  • Trans-Activators
  • Transcription Factors
  • Glutathione Transferase