Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein.
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.
Balasenthil
Seetharaman
S
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Vadlamudi
Ratna K
RK
D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle; D056970:Co-Repressor Proteins; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D004967:Estrogens / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D016196:S Phase; D013997:Time Factors; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D056970:Co-Repressor Proteins; D018076:DNA, Complementary; D004967:Estrogens; C438485:PELP1 protein, human; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D005982:Glutathione Transferase