MNAR-PELP1 and Estrogen Receptor Interaction
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MNAR-PELP1 and Estrogen Receptor Interaction
Estrogen contributes to the development of three of the top five cancers of women--those of the breast, uterus, and ovaries--which together account for an estimated 240,000 new cancer cases a year in the United States alone (Ref.1). The ER (Estrogen Receptor) signaling pathway is implicated in the progression of cancer tumorigenesis and the activity of the hormone receptor is regulated by ligands (Estrogens), and coactivators or corepressors (Ref.2). MNAR (Modulator of Nongenomic Activity Of Estrogen Receptor)/PELP1 (Proline Glutamic Acid-Rich Nuclear Protein)/p160, a recently identified novel coactivator of ERs, has been shown to be amplified and overexpressed in breast cancer cell lines, whose expression in some cases, may be as high as, 3-5 times higher in breast tumors than in normal tissues. MNAR/PELP1 is widely expressed in a variety of E2 (17-Beta Estradiol)-responsive reproductive tissues and is developmentally regulated in mammary glands (Ref.3). It is more clearly described as a scaffold protein belonging to the steroid receptor coactivator family that incorporates ERs, and potentially other nuclear hormone receptors, signaling into the intracellular communication system. MNAR is differentially expressed in various human tissues with the highest expression levels in the mammary glands, testes, and brain. MNAR is predominantly nuclear in localization, contains 10 nuclear receptor interaction motifs, and functions as an ER coactivator in a ligand-dependent manner (Ref.4).

The primary structure of MNAR contains several motifs commonly present in the transcriptional regulators including LXXLL motifs (L being leucine and X any amino acid), zinc finger, and glutamic- and proline-rich regions. It has been established that estrogen has at least two courses of action termed classical or genomic and nongenomic. The classical pathways depend on direct interaction of estrogen with its receptor in the nucleus. Once activated, the ER-ligand complex can directly mediate gene transcription through interaction with the palindromic ERE (Estrogen Response Element) located in the target gene promoters or interact with transcription factors to influence their activity. MNAR enhances ER-dependent transcriptional activation of the ERE (estrogen response element) in a dose-dependent manner. MNAR interacts with general transcriptional cointegrators p300 and CBP (CREB-Binding Protein) for its optimum action (Ref.5). The nonclassical pathways work more rapidly and lead to the activation of the MAPK (Mitogen-Activated Protein Kinase) cascade and other cell proliferation effects. In breast cancer cells, Estrogen treatment activates the nonclassical Src-Ras-ERK pathway, leading to cell cycle progression, which is mediated by MNAR. Although a major portion of the MNAR content of the cell is confined to the nucleus, a portion of it is localized close to the plasma membrane (Ref.1). Otherwise, MNAR-ER complex can be formed in the nucleus and transferred to the cell membrane, or MNAR and ER could be transported from the nucleus independently and take part in the non-genomic cascade. The interaction of ER, MNAR and Src leads to the activation of the MAPKs: ERK1 (Extracellular Signal-Regulated Kinase) and ERK2 that are subsequently transported to the nucleus to activate transcription (Ref.5).

MNAR also contributes to ER-mediated G1/S phase progression, in addition to its role in ER transcriptional regulation. It affects ER-mediated cell cycle progression through both transcriptionally regulating E2-responsive genes (such as Cyclin-D1) and modulating the functions of cell cycle regulators such as Rb. MNAR overexpression results in persistent up-regulation of Cyclin-D1 and increased hyperphosphorylation of Rb (Retinoblastoma susceptibility protein). Rb plays an important role in cell proliferation and differentiation. It inactivates E2F through direct interaction and sequestration. Phosphorylation of Rb by CDKs (Cell Cycle-Dependent Kinases) releases E2F, thus leading to G1/S phase progression (Ref.6). In addition, MNAR-Rb interactions positively modulate both ERE reporter and Cyclin-D1 promoter activities. MNAR interacts with Rb via its C-terminal pocket domain and that regulatory interaction between MNAR and Rb is required for MNAR-mediated maximal ER coactivation functions. MNAR-Rb interactions also play a role in the regulation of specific genes during mammary gland development and differentiation (Ref.3). Because MNAR expression is regulated in breast tumors, its ability to modulate Cyclin-D1 expression provides a functional advantage for ER-positive tumors and plays a role in ER-positive tumor cell proliferation. MNAR overexpression hypersensitizes breast cancer cells to E2 signaling and enhances progression of breast cancer cells to S phase. Overexpression of MNAR may impact the ER-signaling pathways and modulate the responses of estrogen and anti-estrogens in hormone-dependent cancers (Ref.2).