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Atlas of Genetics and Cytogenetics in Oncology and Haematology INI ST -CNRS OPEN ACCESS JOURNAL Gene Section Short Communication MED28 (mediator complex subunit 28) Ming-Fen Lee, Chun-Yin Huang Department of Nutrition and Health Sciences, Chang Jung Christian University, 396 Sec 1 Changrong Rd, Gueiren Dist, Tainan, Taiwan 71101, China (MFL), Department of Nutrition, China Medical University, 91 Hsueh-Shih Road, Taichung, Taiwan 40402, China (CYH) Published in Atlas Database: July 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/MED28ID50131ch4p15.html DOI: 10.4267/2042/48468 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology MED28 was also identified as a merlin-interacting Identity protein by yeast two-hybrid screen (Wiederhold et al., Other names: 1500003D12Rik, EG1, magicin 2004), where merlin, the neurofibromatosis 2 (NF2) HGNC (Hugo): MED28 tumor suppressor protein, belongs to the ezrin-radixin- Location: 4p15.32 moesin (ERM) family members. Affinity-binding assays demonstrated that MED28 interacted with the DNA/RNA SH3 domains of Grb2 (Wiederhold et al., 2004). Accordingly, MED28 was also named as magicin, Note merlin and Grb2 interacting cytoskeletal protein MED28 mRNA is identical to AF317679, AF358829, (Wiederhold et al., 2004). and AF321617 with the respective size of ~1, ~1.3, and In addition, several Src family members, including Src, ~3.2 kb (Wiederhold et al., 2004). They vary in the Fyn, and Lck, are also MED28-associated partners (Lee untranslated region, but share the same protein product. et al., 2006; Lu et al., 2006). Therefore, MED28/magicin/EG-1 may function as an Protein adaptor/scaffold to relay cellular signaling (Lee et al., 2006). Description Furthermore, MED28 is also found in the nucleus The full-length MED28 protein consists of 178 amino where it is presumably involved in gene transcription as acids with a predicted molecular weight ~20 kDa part of the Mediator complex (Sato et al., 2004). It is (Wiederhold et al., 2004). MED28, an evolutionaly likely that MED28 shuttles between nucleus, conserved protein, was identified as an endothelial- cytoskeleton, and cytoplasm to convey its physiological derived gene, EG-1 (Liu et al., 2002). role. Figure 1. Diagram of pre-mRNA of MED28. The black bars are exons. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) 28 MED28 (mediator complex subunit 28) Lee MF, Huang CY Figure 2. MED28 interacting proteins. Expression mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1) in MCF7 cells (Huang et al., 2012). MED28 is expressed in multiple human tissues In addition, overexpression of MED28 resulted in the (Wiederhold et al., 2004), with high expression in liver, activation of c-Src (Lu et al., 2006) and MED28 can be placenta, and testis (Liu et al., 2002). phosphorylated at Y64 by Fyn, a Src family member MED28-interacting proteins: merlin, actin, Grb2 (Lee et al., 2006). These data indicate that MED28 may (Wiederhold et al., 2004), Fyn, Lck, Src (Lee et al., function as a regulator of cellular signal transduction 2006; Lu et al., 2006), Mediator subunits (Sato et al., pathways. 2004). Cell proliferation: Localisation Ectopic overexpression of MED28 resulted in enhanced Cytoskeleton, cytoplasm, and nucleus (Sato et al., cell growth in immortal human embryonic kidney 2004; Wiederhold et al., 2004). (HEK) 293 cells, and breast cancer cell lines, MCF7 and MDA-MB-231 (Lu et al., 2005). The HEK293 Function xenograft tumor growth was also stimulated in MED28 may be involved in the regulation of numerous MED28-overexpressing cells (Lu et al., 2005). biological processes, including transcriptional Smooth muscle cell differentiation: regulation, cytoskeletal organization, signal MED28 functions a repressor of smooth muscle cell transduction, cell proliferation, differentiation, (SMC) differentiation (Beyer et al., 2007). MED28- angiogenesis, and migration (Beyer et al., 2007; Huang specific knockdown resulted in up-regulation of several et al., 2012; Liu et al., 2002; Wiederhold et al., 2004; SMC-related genes and SMC phenotype, whereas Yoon et al., 2010; Zhang et al., 2004). ectopic expression of MED28 reversed the SMC Transcription regulation: morphology induced by MED28 knockdown (Beyer et The Mediator complex is a set of protein coactivators al., 2007). that bridges DNA-binding transcription factors to Angiogenesis: transcriptional activation of the RNA polymerase II MED28 expression was increased by two-fold in (pol II). MED28 was identified as a subunit of the human umbilical vein endothelial cells (HUVECs) mammalian Mediator complex by the multidimensional treated with either tumor conditioned media or specific protein identification technology (MudPIT) (Sato et al., angiogenic factors (Liu et al., 2002). This observation 2004). This identification indicates a role of MED28 in suggests a role of MED28 in angiogenesis. the regulation of gene transcription. Cell migration: Cytoskeletal organization: The role of MED28 in cell migration was demonstrated The implication of MED28 in cytoskeletal re- in both estrogen receptor (ER)-positive and negative organization was based on the observation that human breast cancer cell lines (Huang et al., 2012; Lee MED28, similar to merlin, co-localizes with the actin et al., 2011). cytoskeleton as determined by cofractionation, Ectopic expression of MED28 increased cell migration immunofluorescence and electron microscopy and invasion in MCF7 and MDA-MB-231 breast (Wiederhold et al., 2004). cancer cells (Huang et al., 2012; Lee et al., 2011). Signal transduction: Investigation of the underlying mechanisms revealed Ectopic expression of MED28 led to increased that MED28 activates epidermal growth factor (EGF)- phosphorylation of mitogen-activated protein kinases stimulated migration through induction of matrix (MAPK) (Lu et al., 2005). In contrast, MED28-specific metalloproteinase 9 (MMP9) in EGFR-overexpressing knockdown resulted in decreased expression of MDA-MB-231 cells (Lee et al., 2011). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) 29 MED28 (mediator complex subunit 28) Lee MF, Huang CY Figure 3. Biological functions of MED28. In addition, MED28 can also regulate cell migration Prognosis through the mitogen-activated protein kinase kinase 1 The evidence supporting MED28 as a prognostic factor (MAP2K1; MEK1)-dependent MMP2 activation, is emerging. MED28 peptide was detectable in serum which is independent of EGF stimulation (Huang et al., and urine of a small set of breast cancer patients (Lu et 2012). These lines of evidence support the role of al., 2007). In addition, statistical analysis on the MED28 in cell migration, implying that MED28 might correlation between MED28 and survival time or time- be responsible for cancer metastasis. to-relapse indicates that MED28 is a significant Homology predictor of malignant breast cancer (Yoon et al., 2010). MED28 has significant homology to a mouse cDNA (94%), fish, and a fly cDNA (31%) (Liu et al., 2002; References Wiederhold et al., 2004). The mouse MED28 gene is located on chromosome 5 (45520229..45529284). Liu C, Zhang L, Shao ZM, Beatty P, Sartippour M, Lane TF, Barsky SH, Livingston E, Nguyen M. Identification of a novel endothelial-derived gene EG-1. Biochem Biophys Res Implicated in Commun. 2002 Jan 11;290(1):602-12 Various cancers Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway Note JW, Conaway RC. A set of consensus mammalian mediator MED28 expression is elevated in cancers including subunits identified by multidimensional protein identification breast, colorectal, and prostate cancers, suggesting a technology. Mol Cell. 2004 Jun 4;14(5):685-91 role of MED28 in malignant phenotype of epithelial- Wiederhold T, Lee MF, James M, Neujahr R, Smith N, Murthy derived cancers (Liu et al., 2002; Zhang et al., 2004). A, Hartwig J, Gusella JF, Ramesh V. Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor Further tissue microarray (TMA) analysis on a set of merlin and Grb2. Oncogene. 2004 Nov 18;23(54):8815-25 breast cancer population also showed elevated MED28 expression in the ductal carcinoma in situ (DCIS) and Zhang L, Maul RS, Rao J, Apple S, Seligson D, Sartippour M, Rubio R, Brooks MN. Expression pattern of the novel gene invasive ductal carcinoma lesions (Yoon et al., 2010). EG-1 in cancer. Clin Cancer Res. 2004 May 15;10(10):3504-8 Such elevated MED28 expression independently Lu M, Zhang L, Maul RS, Sartippour MR, Norris A, Whitelegge predicts poor survival (Yoon et al., 2010). These data J, Rao JY, Brooks MN. The novel gene EG-1 stimulates indicate that MED28 may be a potential therapeutic cellular proliferation. Cancer Res. 2005 Jul 15;65(14):6159-66 target in cancer intervention. Indeed, MED28 Lee MF, Beauchamp RL, Beyer KS, Gusella JF, Ramesh V. suppression via either siRNA lentivirus or polyclonal Magicin associates with the Src-family kinases and is antibody resulted in decreased growth of both MCF7 phosphorylated upon CD3 stimulation. Biochem Biophys Res and MDA-MB-231 cell lines and their corresponding Commun. 2006 Sep 29;348(3):826-31 xenograft tumors in mice (Lu et al., 2007). Lu M, Zhang L, Sartippour MR, Norris AJ, Brooks MN. EG-1 Furthermore, the in vitro application of phytochemical interacts with c-Src and activates its signaling pathway. Int J resveratrol potently inhibited EGF-stimulated cell Oncol. 2006 Oct;29(4):1013-8 migration via suppression of MED28 in MDA-MB-231 Beyer KS, Beauchamp RL, Lee MF, Gusella JF, Näär AM, breast cancer cells (Lee et al., 2011). Ramesh V. Mediator subunit MED28 (Magicin) is a repressor Atlas Genet Cytogenet Oncol Haematol. 2013; 17(1) 30 MED28 (mediator complex subunit 28) Lee MF, Huang CY of smooth muscle cell differentiation. J Biol Chem. 2007 Nov epidermal growth factor (EGF)-induced migration in MDA-MB- 2;282(44):32152-7 231 human breast cancer cells. J Agric Food Chem. 2011 Nov 9;59(21):11853-61 Lu M, Sartippour MR, Zhang L, Norris AJ, Brooks MN.
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  • Elevated MED28 Expression Predicts Poor Outcome in Women with Breast Cancer

    Elevated MED28 Expression Predicts Poor Outcome in Women with Breast Cancer

    UCLA UCLA Previously Published Works Title Elevated MED28 expression predicts poor outcome in women with breast cancer Permalink https://escholarship.org/uc/item/2pw3410d Journal BMC Cancer, 10(1) ISSN 1471-2407 Authors Yoon, Nam K Maresh, Erin L Elshimali, Yahya et al. Publication Date 2010-06-28 DOI http://dx.doi.org/10.1186/1471-2407-10-335 Supplemental Material https://escholarship.org/uc/item/2pw3410d#supplemental Peer reviewed eScholarship.org Powered by the California Digital Library University of California Yoon et al. BMC Cancer 2010, 10:335 http://www.biomedcentral.com/1471-2407/10/335 RESEARCH ARTICLE Open Access ElevatedResearch article MED28 expression predicts poor outcome in women with breast cancer Nam K Yoon1, Erin L Maresh1, Yahya Elshimali1, Ai Li2, Steve Horvath2,3,4, David B Seligson1,4, David Chia1,4 and Lee Goodglick*1,4 Abstract Background: MED28 (also known as EG-1 and magicin) has been implicated in transcriptional control, signal regulation, and cell proliferation. MED28 has also been associated with tumor progression in in vitro and in vivo models. Here we examined the association of MED28 expression with human breast cancer progression. Methods: Expression of MED28 protein was determined on a population basis using a high-density tissue microarray consisting of 210 breast cancer patients. The association and validation of MED28 expression with histopathological subtypes, clinicopathological variables, and disease outcome was assessed. Results: MED28 protein expression levels were increased in ductal carcinoma in situ and invasive ductal carcinoma of the breast compared to non-malignant glandular and ductal epithelium. Moreover, MED28 was a predictor of disease outcome in both univariate and multivariate analyses with higher expression predicting a greater risk of disease-related death.