Disease relevance of PA2G4

• These findings suggest that Ebp1 is a previously unrecognized therapeutic target for treatment of hormone refractory prostate cancer [1].
• Furthermore, we demonstrate that PA2G4 expression can serve as a novel prognostic factor for disease-free survival in two independent breast cancer patient cohorts [2].
• DNase I footprinting indicates that both 10-bp sites on the same molecule, located between -80 and -105 on the HIV-1 long terminal repeat, can be occupied by EBP1, while dimethyl sulfate protection and methylation interference experiments indicate which purine bases are in contact with the protein [3].
• Interaction of enhancer-binding protein EBP1 (NF-kappa B) with the human immunodeficiency virus type 1 enhancer [3].

High impact information on PA2G4

• EBP1 regulates organ size through cell growth and proliferation in plants [4].
• EBP1 is required for expression of cell cycle genes; CyclinD3;1, ribonucleotide reductase 2 and the cyclin-dependent kinase B1;1 [4].
• We argue that EBP1 is a conserved, dose-dependent regulator of cell growth that is connected to meristematic competence and cell proliferation via regulation of RBR1 level [4].
• The regulation of these genes by EBP1 is dose and auxin dependent and might rely on the effect of EBP1 to reduce RBR1 protein level [4].
• Plant EBP1 levels are tightly regulated; gene expression is highest in developing organs and correlates with genes involved in ribosome biogenesis and function [4].

Biological context of PA2G4

• Molecular cloning and mapping of a human cDNA (PA2G4) that encodes a protein highly homologous to the mouse cell cycle protein p38-2G4 [5].
• This novel gene (called PA2G4) belongs to a gene family with members in several chromosome regions: 3q24-q25, 6q22, 9q21, 12q13, 18q12, 20p12 and Xq25 [5].
• Androgens failed to stimulate either the growth of ebp1 transfectants or transcription of AR-regulated reporter genes in these cells [1].
• The C-terminal domain of Ebp1, responsible for its ability to repress transcription and arrest cell growth, was necessary and sufficient for binding Sin3A [6].
• In this study, we demonstrate, using several natural AR-regulated promoters, that Ebp1 repressed transcriptional activation of wild-type AR in prostate cancer cell lines [7].

Anatomical context of PA2G4

• Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines [6].
• These results strongly suggest that PA2G4 may have an important role on the regulation of DNA replication in eukaryotic cells [8].
• Here, we show that Ebp1 possesses two different isoforms, p48 and p42, which differentially mediate PC12 cell survival and differentiation [9].
• Here, we report cloning and characterizing of a novel mitogen-inducible gene from murine macrophages that predicts a cell cycle-specifically modulated nuclear protein of 38 kDa, designated p38-2G4. p38-2G4 displayed a speckled pattern of varying fluorescence intensity confined to the nucleus, but sparing the nucleoli [10].
• Ebp1 was localized to both the nucleus and the cytoplasm of logarithmically growing AU565 breast cancer cells and HeLa cells as determined by confocal immunofluorescent microscopy [11].

Associations of PA2G4 with chemical compounds

• Ebp1 expression was reduced in cells that had become androgen-independent [1].
• EBP1 protein is stabilised by auxin [4].
• The presence of bases which exhibit increased rates of dimethyl sulfate-induced methylation in the presence of EBP1 indicate that interaction of EBP1 with its recognition site is accompanied by distortion of the DNA double helix [3].
• Supporting this conclusion is the observation that the polyamine spermidine dramatically increases EBP1 binding to its cognate site on the DNA [3].
• The TH-induced up-regulation of RcC/EBP-1 mRNAs precedes the up-regulation of liver-specific urea cycle enzyme mRNAs by 6 to 12 hours [12].

Physical interactions of PA2G4

• Using the yeast two-hybrid system, we have isolated an ErbB-3 binding protein (Ebp1) that interacts with the juxtamembrane domain of ErbB-3 [13].
• Ebp1 bound E2F1 indirectly via Rb in lysates of MCF-7 cells [11].

Regulatory relationships of PA2G4

• The ErbB3 binding protein Ebp1 interacts with Sin3A to repress E2F1 and AR-mediated transcription [6].
• The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells [1].

Other interactions of PA2G4

• The interaction of Ebp1 with ErbB-3 was examined in vitro and in vivo [13].
• Repression of E2F1-mediated transcription by the ErbB3 binding protein Ebp1 involves histone deacetylases [14].
• To validate the NBS/2DE/MS results, we used immunoblotting to confirm GRP78, CK19, and PA2G4 as bona fide TAM-regulated proteins [2].
• Ectopic expression of ebp1 led to a more differentiated phenotype in AU565 breast cancer cells, as evidenced by increased expression of lipid droplets and of the milk protein casein [15].

Analytical, diagnostic and therapeutic context of PA2G4

• Chromatin immunoprecipitation assays revealed that Ebp1 was recruited to the prostate-specific antigen gene promoter in response to the androgen antagonist bicalutamide, suggesting that Ebp1 directly affected the expression of AR-regulated genes in response to androgen antagonists [1].
• Using microarray analysis, we identified six endogenous AR target genes, including the AR itself, that are down-regulated by ebp1 overexpression [1].
• Additionally, p38-2G4 expression vanished in G0-arrested cells and was restored after release from growth arrest. p38-2G4 conserved in vertebrates by means of immunofluorescence data contains a number of putative phosphorylation sites, a cryptic nuclear localization signal, and an amphipathic helical domain [10].
• Ebp1, an ErbB-3 binding protein, translocates from the cytoplasm to the nucleus of human breast cancer cells after treatment with the ErbB-3 ligand, heregulin [15].
• These results, coupled with in situ hybridization studies, suggest that RcC/EBP-1 mRNAs encode a transcription factor which may play an early role(s) in the terminal differentiation and/or reprogramming of gene expression in this tadpole's liver cells during both spontaneous and TH-induced metamorphosis [12].

References