Disease relevance of PELP1

• PELP1 promoted a tamoxifen-mediated agonistic action in endometrial, but not in breast cancer cells [1].
• However, in endometrial cancer cells, endogenous PELP1 is also required for optimal ligand-mediated transcription and proliferation responses [1].
• In transient transfection assays, E2 upregulated PELP1 promoter activity in breast, endometrial and osteosarcoma model cancer cell lines in an ICI 182,780-sensitive manner [2].
• Emerging evidence suggests that PELP1/MNAR increases E2-mediated cell proliferation and participates in E2-mediated tumorigenesis and metastasis [3].
• Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein [4].

High impact information on PELP1

• These data reveal that MNAR mediates the crosstalk between two important classes of signal transducing molecules and suggest that ER "genomic" and "nongenomic" activities are interrelated [5].
• We have identified a previously uncharacterized nuclear receptor-interacting protein designated as modulator of nongenomic activity of estrogen receptor (MNAR) [5].
• We also show that MNAR, through activation of the Src/Erk phosphorylation cascade, affects ER transcriptional activity and ultimately ER-mediated gene expression [5].
• A pine extensin-like protein (PELP) has been localized in metabolically active cells of differentiating xylem and in mature wood of loblolly pine (Pinus taeda L.). This proline-rich glycosylated protein was purified from cell walls of differentiating xylem by differential solubility and gel electrophoresis [6].
• Functional implications of altered subcellular localization of PELP1 in breast cancer cells [7].

Chemical compound and disease context of PELP1

• We found that in MCF-7 breast cancer cells, E2 upregulated PELP1 expression threefold and that this upregulation was reduced by antiestrogen [2].
• 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 [4].
• We investigated the role of PELP1 in resveratrol-induced autophagy in lung cancer and salivary gland adenocarcinoma cell lines [8].

Biological context of PELP1

• Cloning and analysis of the 2-kb PELP1 promoter region revealed two estrogen-responsive element (ERE) half sites in the PELP1 promoter region [2].
• In addition, PELP1 interacted with epidermal growth factor receptors and participated in growth factor-mediated ER transactivation functions [7].
• Using deletion analysis, we have identified the PELP1 COOH-terminal region as the histone 1 binding site [9].
• Our results provide novel insights about the transcription regulation of PELP1 and suggest that PELP1 participates in chromatin remodeling activity via displacement of histone 1 in cancer cells [9].
• Using phosphorylation site-specific pRb antibodies, we identified Ser-807/Ser-811 of pRb as a potential target site of PELP1 [4].

Anatomical context of PELP1

• PELP1 expression also retarded the proliferation of mouse fibroblast cell lines in which there was no detectable ER [10].
• We characterized the expression and localization of PELP1 in both benign and cancerous endometrium [1].
• PELP1 is expressed in both the stroma and epithelial cells [1].
• PELP1 expression is developmentally regulated in mammary glands and overexpressed in breast tumors [2].
• Subnuclear fractionation showed PELP1 association with chromatin and nuclear matrix fractions [9].

Associations of PELP1 with chemical compounds

• The N-terminal leucine-abundant region of PELP1 was observed to interact with HDAC2 and exhibited repressive activity when tethered to the chromatin [10].
• PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) (also known as the modulator of nongenomic activity of estrogen receptor) plays a role in genomic functions of the estrogen receptor via histone interactions and in nongenomic functions via its influence on the MAPK-Src pathway [11].
• In this study, we examined whether PELP1 expression is modulated by steroid hormone 17beta-estradiol (E2)-ER pathway [2].
• We also found that E2 modulated PELP1 levels in an actinomycin-D-sensitive manner, suggesting transcriptional regulation [2].
• PELP1 overexpression increased the micrococcal nuclease sensitivity of estrogen response element-containing nucleosomes [9].

Physical interactions of PELP1

• The PELP1 mutant lacking histone 1-binding domain acts as a dominant-negative and blocks estrogen receptor alpha-mediated transcription [9].
• PELP1 interacts with ERalpha and also with general transcriptional coactivators p300 and cAMP response element-binding protein-binding protein [12].
• PELP1 was found to be a binding partner of RXRalpha, and the binding interactions were confirmed both in vitro and in vivo [13].

Regulatory relationships of PELP1

• The PELP1 promoter was similarly upregulated by both ERalpha and ERbeta and differentially regulated by selective estrogen receptor modulators in a cell line-dependent manner [2].
• Mapping studies reveal that both the A/B domain and Y537 of ERalpha are required for MNAR-induced activation of ER transcriptional activity [14].
• In conclusion, our results suggest that altered localization of PELP1 promotes heightened sensitivity to TNF-alpha in MCF-7 cells, paving the way for developing new treatment strategies for tumors with cytoplasmic PELP1 expression [15].

Other interactions of PELP1

• The transcriptional corepressor, PELP1, recruits HDAC2 and masks histones using two separate domains [10].
• PELP1 / MNAR staining was predominantly cytoplasmic whereas ER beta staining was nuclear and occasionally cytoplasmic in tumor cells [16].
• 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 [4].
• Ligand stimulation promoted recruitment of PELP1 to 17beta-estradiol responsive promoters, its colocalization with acetylated H3, and increased PELP1-associated histone acetyltransferase enzymatic activity [9].
• The primary structure of PELP1 consists of several motifs present in most transcriptional regulators including nine NR-interacting boxes (LXXLL motifs), a zinc finger, and glutamic acid- and proline-rich regions [12].

Analytical, diagnostic and therapeutic context of PELP1

• We demonstrated the recruitment of ER to the PELP1 promoter in vitro using EMSA assays and in vivo using a chromatin immunoprecipitation assay [2].
• We investigated the differential expression of the PELP1 / MNAR and the ERs alpha and beta proteins in SDCs, using Western blotting and immunohistochemistry [16].
• Western blot analysis of 7 paired normal and tumor specimens showed increased expression of PELP1 / MNAR and ER beta in 3 and 4 of the SDCs, respectively [16].
• Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha [12].
• An electrophoretic mobility shift assay showed greater formation and stability of RXRalpha homodimers on consensus oligonucleotides in PELP1-overexpressing clones in comparison to the pcDNA clones [13].

References