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MED28 (mediator complex subunit 28)

Written2012-07Ming-Fen Lee, Chun-Yin Huang
Department of Nutrition, 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)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesmediator of RNA polymerase II transcription
Alias_symbol (synonym)EG1
DKFZP434N185
magicin
Other alias1500003D12Rik
HGNC (Hugo) MED28
LocusID (NCBI) 80306
Atlas_Id 50131
Location 4p15.32  [Link to chromosome band 4p15]
Location_base_pair Starts at 17614628 and ends at 17625628 bp from pter ( according to hg19-Feb_2009)  [Mapping MED28.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
EIF1 (17q21.2) / MED28 (4p15.32)MED28 (4p15.32) / GINS2 (16q24.1)

DNA/RNA

Note MED28 mRNA is identical to AF317679, AF358829, and AF321617 with the respective size of ~1, ~1.3, and ~3.2 kb (Wiederhold et al., 2004). They vary in the untranslated region, but share the same protein product.
 
  Figure 1. Diagram of pre-mRNA of MED28. The black bars are exons.

Protein

Description The full-length MED28 protein consists of 178 amino acids with a predicted molecular weight ~20 kDa (Wiederhold et al., 2004). MED28, an evolutionaly conserved protein, was identified as an endothelial-derived gene, EG-1 (Liu et al., 2002). MED28 was also identified as a merlin-interacting protein by yeast two-hybrid screen (Wiederhold et al., 2004), where merlin, the neurofibromatosis 2 (NF2) tumor suppressor protein, belongs to the ezrin-radixin-moesin (ERM) family members. Affinity-binding assays demonstrated that MED28 interacted with the SH3 domains of Grb2 (Wiederhold et al., 2004). Accordingly, MED28 was also named as magicin, merlin and Grb2 interacting cytoskeletal protein (Wiederhold et al., 2004). In addition, several Src family members, including Src, Fyn, and Lck, are also MED28-associated partners (Lee et al., 2006; Lu et al., 2006). Therefore, MED28/magicin/EG-1 may function as an adaptor/scaffold to relay cellular signaling (Lee et al., 2006). Furthermore, MED28 is also found in the nucleus where it is presumably involved in gene transcription as part of the Mediator complex (Sato et al., 2004). It is likely that MED28 shuttles between nucleus, cytoskeleton, and cytoplasm to convey its physiological role.
Expression MED28 is expressed in multiple human tissues (Wiederhold et al., 2004), with high expression in liver, placenta, and testis (Liu et al., 2002).
MED28-interacting proteins: merlin, actin, Grb2 (Wiederhold et al., 2004), Fyn, Lck, Src (Lee et al., 2006; Lu et al., 2006), Mediator subunits (Sato et al., 2004).
 
  Figure 2. MED28 interacting proteins.
Localisation Cytoskeleton, cytoplasm, and nucleus (Sato et al., 2004; Wiederhold et al., 2004).
Function MED28 may be involved in the regulation of numerous biological processes, including transcriptional regulation, cytoskeletal organization, signal transduction, cell proliferation, differentiation, angiogenesis, and migration (Beyer et al., 2007; Huang et al., 2012; Liu et al., 2002; Wiederhold et al., 2004; Yoon et al., 2010; Zhang et al., 2004).

Transcription regulation:
The Mediator complex is a set of protein coactivators that bridges DNA-binding transcription factors to transcriptional activation of the RNA polymerase II (pol II). MED28 was identified as a subunit of the mammalian Mediator complex by the multidimensional protein identification technology (MudPIT) (Sato et al., 2004). This identification indicates a role of MED28 in the regulation of gene transcription.

Cytoskeletal organization:
The implication of MED28 in cytoskeletal re-organization was based on the observation that MED28, similar to merlin, co-localizes with the actin cytoskeleton as determined by cofractionation, immunofluorescence and electron microscopy (Wiederhold et al., 2004).

Signal transduction:
Ectopic expression of MED28 led to increased phosphorylation of mitogen-activated protein kinases (MAPK) (Lu et al., 2005). In contrast, MED28-specific knockdown resulted in decreased expression of mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1) in MCF7 cells (Huang et al., 2012). In addition, overexpression of MED28 resulted in the activation of c-Src (Lu et al., 2006) and MED28 can be phosphorylated at Y64 by Fyn, a Src family member (Lee et al., 2006). These data indicate that MED28 may function as a regulator of cellular signal transduction pathways.

Cell proliferation:
Ectopic overexpression of MED28 resulted in enhanced cell growth in immortal human embryonic kidney (HEK) 293 cells, and breast cancer cell lines, MCF7 and MDA-MB-231 (Lu et al., 2005). The HEK293 xenograft tumor growth was also stimulated in MED28-overexpressing cells (Lu et al., 2005).

Smooth muscle cell differentiation:
MED28 functions a repressor of smooth muscle cell (SMC) differentiation (Beyer et al., 2007). MED28-specific knockdown resulted in up-regulation of several SMC-related genes and SMC phenotype, whereas ectopic expression of MED28 reversed the SMC morphology induced by MED28 knockdown (Beyer et al., 2007).

Angiogenesis:
MED28 expression was increased by two-fold in human umbilical vein endothelial cells (HUVECs) treated with either tumor conditioned media or specific angiogenic factors (Liu et al., 2002). This observation suggests a role of MED28 in angiogenesis.

Cell migration:
The role of MED28 in cell migration was demonstrated in both estrogen receptor (ER)-positive and negative human breast cancer cell lines (Huang et al., 2012; Lee et al., 2011). Ectopic expression of MED28 increased cell migration and invasion in MCF7 and MDA-MB-231 breast cancer cells (Huang et al., 2012; Lee et al., 2011). Investigation of the underlying mechanisms revealed that MED28 activates epidermal growth factor (EGF)-stimulated migration through induction of matrix metalloproteinase 9 (MMP9) in EGFR-overexpressing MDA-MB-231 cells (Lee et al., 2011). In addition, MED28 can also regulate cell migration through the mitogen-activated protein kinase kinase 1 (MAP2K1; MEK1)-dependent MMP2 activation, which is independent of EGF stimulation (Huang et al., 2012). These lines of evidence support the role of MED28 in cell migration, implying that MED28 might be responsible for cancer metastasis.

 
  Figure 3. Biological functions of MED28.
Homology MED28 has significant homology to a mouse cDNA (94%), fish, and a fly cDNA (31%) (Liu et al., 2002; Wiederhold et al., 2004). The mouse MED28 gene is located on chromosome 5 (45520229..45529284).

Implicated in

Note
  
Entity Various cancers
Note MED28 expression is elevated in cancers including breast, colorectal, and prostate cancers, suggesting a role of MED28 in malignant phenotype of epithelial-derived cancers (Liu et al., 2002; Zhang et al., 2004). Further tissue microarray (TMA) analysis on a set of breast cancer population also showed elevated MED28 expression in the ductal carcinoma in situ (DCIS) and invasive ductal carcinoma lesions (Yoon et al., 2010). Such elevated MED28 expression independently predicts poor survival (Yoon et al., 2010). These data indicate that MED28 may be a potential therapeutic target in cancer intervention. Indeed, MED28 suppression via either siRNA lentivirus or polyclonal antibody resulted in decreased growth of both MCF7 and MDA-MB-231 cell lines and their corresponding xenograft tumors in mice (Lu et al., 2007). Furthermore, the in vitro application of phytochemical resveratrol potently inhibited EGF-stimulated cell migration via suppression of MED28 in MDA-MB-231 breast cancer cells (Lee et al., 2011).
Prognosis The evidence supporting MED28 as a prognostic factor is emerging. MED28 peptide was detectable in serum and urine of a small set of breast cancer patients (Lu et al., 2007). In addition, statistical analysis on the correlation between MED28 and survival time or time-to-relapse indicates that MED28 is a significant predictor of malignant breast cancer (Yoon et al., 2010).
  

Bibliography

Mediator subunit MED28 (Magicin) is a repressor of smooth muscle cell differentiation.
Beyer KS, Beauchamp RL, Lee MF, Gusella JF, Naar AM, Ramesh V.
J Biol Chem. 2007 Nov 2;282(44):32152-7. Epub 2007 Sep 11.
PMID 17848560
 
MED28 regulates MEK1-dependent cellular migration in human breast cancer cells.
Huang CY, Chou YH, Hsieh NT, Chen HH, Lee MF.
J Cell Physiol. 2012 Dec;227(12):3820-7. doi: 10.1002/jcp.24093.
PMID 22495818
 
Magicin associates with the Src-family kinases and is phosphorylated upon CD3 stimulation.
Lee MF, Beauchamp RL, Beyer KS, Gusella JF, Ramesh V.
Biochem Biophys Res Commun. 2006 Sep 29;348(3):826-31. Epub 2006 Jul 31.
PMID 16899217
 
Resveratrol modulates MED28 (Magicin/EG-1) expression and inhibits epidermal growth factor (EGF)-induced migration in MDA-MB-231 human breast cancer cells.
Lee MF, Pan MH, Chiou YS, Cheng AC, Huang H.
J Agric Food Chem. 2011 Nov 9;59(21):11853-61. Epub 2011 Oct 17.
PMID 21942447
 
Identification of a novel endothelial-derived gene EG-1.
Liu C, Zhang L, Shao ZM, Beatty P, Sartippour M, Lane TF, Barsky SH, Livingston E, Nguyen M.
Biochem Biophys Res Commun. 2002 Jan 11;290(1):602-12.
PMID 11779215
 
Targeted inhibition of EG-1 blocks breast tumor growth.
Lu M, Sartippour MR, Zhang L, Norris AJ, Brooks MN.
Cancer Biol Ther. 2007 Jun;6(6):936-41. Epub 2007 Mar 26.
PMID 17568184
 
EG-1 interacts with c-Src and activates its signaling pathway.
Lu M, Zhang L, Sartippour MR, Norris AJ, Brooks MN.
Int J Oncol. 2006 Oct;29(4):1013-8.
PMID 16964398
 
A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology.
Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC.
Mol Cell. 2004 Jun 4;14(5):685-91.
PMID 15175163
 
Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2.
Wiederhold T, Lee MF, James M, Neujahr R, Smith N, Murthy A, Hartwig J, Gusella JF, Ramesh V.
Oncogene. 2004 Nov 18;23(54):8815-25.
PMID 15467741
 
Elevated MED28 expression predicts poor outcome in women with breast cancer.
Yoon NK, Maresh EL, Elshimali Y, Li A, Horvath S, Seligson DB, Chia D, Goodglick L.
BMC Cancer. 2010 Jun 28;10:335.
PMID 20584319
 
Expression pattern of the novel gene EG-1 in cancer.
Zhang L, Maul RS, Rao J, Apple S, Seligson D, Sartippour M, Rubio R, Brooks MN.
Clin Cancer Res. 2004 May 15;10(10):3504-8.
PMID 15161708
 

Citation

This paper should be referenced as such :
Lee, MF ; Huang, CY
MED28 (mediator complex subunit 28)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(1):28-31.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MED28ID50131ch4p15.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  i(4p) in myeloid malignancies


External links

Nomenclature
HGNC (Hugo)MED28   24628
Cards
AtlasMED28ID50131ch4p15
Entrez_Gene (NCBI)MED28  80306  mediator complex subunit 28
Aliases1500003D12Rik; EG1; magicin
GeneCards (Weizmann)MED28
Ensembl hg19 (Hinxton)ENSG00000118579 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000118579 [Gene_View]  chr4:17614628-17625628 [Contig_View]  MED28 [Vega]
ICGC DataPortalENSG00000118579
TCGA cBioPortalMED28
AceView (NCBI)MED28
Genatlas (Paris)MED28
WikiGenes80306
SOURCE (Princeton)MED28
Genetics Home Reference (NIH)MED28
Genomic and cartography
GoldenPath hg38 (UCSC)MED28  -     chr4:17614628-17625628 +  4p15.32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MED28  -     4p15.32   [Description]    (hg19-Feb_2009)
EnsemblMED28 - 4p15.32 [CytoView hg19]  MED28 - 4p15.32 [CytoView hg38]
Mapping of homologs : NCBIMED28 [Mapview hg19]  MED28 [Mapview hg38]
OMIM610311   
Gene and transcription
Genbank (Entrez)AF317678 AF317679 AF317680 AF318059 AF358829
RefSeq transcript (Entrez)NM_025205
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MED28
Cluster EST : UnigeneHs.731966 [ NCBI ]
CGAP (NCI)Hs.731966
Alternative Splicing GalleryENSG00000118579
Gene ExpressionMED28 [ NCBI-GEO ]   MED28 [ EBI - ARRAY_EXPRESS ]   MED28 [ SEEK ]   MED28 [ MEM ]
Gene Expression Viewer (FireBrowse)MED28 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)80306
GTEX Portal (Tissue expression)MED28
Human Protein AtlasENSG00000118579-MED28 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H204   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9H204  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9H204
Splice isoforms : SwissVarQ9H204
PhosPhoSitePlusQ9H204
Domains : Interpro (EBI)Mediator_Med28   
Domain families : Pfam (Sanger)Med28 (PF11594)   
Domain families : Pfam (NCBI)pfam11594   
Conserved Domain (NCBI)MED28
DMDM Disease mutations80306
Blocks (Seattle)MED28
SuperfamilyQ9H204
Human Protein Atlas [tissue]ENSG00000118579-MED28 [tissue]
Peptide AtlasQ9H204
HPRD14381
IPIIPI00097532   IPI00966840   
Protein Interaction databases
DIP (DOE-UCLA)Q9H204
IntAct (EBI)Q9H204
FunCoupENSG00000118579
BioGRIDMED28
STRING (EMBL)MED28
ZODIACMED28
Ontologies - Pathways
QuickGOQ9H204
Ontology : AmiGOactin binding  protein binding  nucleoplasm  transcription, DNA-templated  regulation of transcription, DNA-templated  membrane  mediator complex  stem cell population maintenance  cortical actin cytoskeleton  negative regulation of smooth muscle cell differentiation  
Ontology : EGO-EBIactin binding  protein binding  nucleoplasm  transcription, DNA-templated  regulation of transcription, DNA-templated  membrane  mediator complex  stem cell population maintenance  cortical actin cytoskeleton  negative regulation of smooth muscle cell differentiation  
REACTOMEQ9H204 [protein]
REACTOME PathwaysR-HSA-381340 [pathway]   
NDEx NetworkMED28
Atlas of Cancer Signalling NetworkMED28
Wikipedia pathwaysMED28
Orthology - Evolution
OrthoDB80306
GeneTree (enSembl)ENSG00000118579
Phylogenetic Trees/Animal Genes : TreeFamMED28
HOVERGENQ9H204
HOGENOMQ9H204
Homologs : HomoloGeneMED28
Homology/Alignments : Family Browser (UCSC)MED28
Gene fusions - Rearrangements
Fusion : MitelmanEIF1/MED28 [17q21.2/4p15.32]  [t(4;17)(p15;q21)]  
Fusion: TCGA_MDACCEIF1 17q21.2 MED28 4p15.32 BRCA
Tumor Fusion PortalMED28
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMED28 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MED28
dbVarMED28
ClinVarMED28
1000_GenomesMED28 
Exome Variant ServerMED28
ExAC (Exome Aggregation Consortium)ENSG00000118579
GNOMAD BrowserENSG00000118579
Genetic variants : HAPMAP80306
Genomic Variants (DGV)MED28 [DGVbeta]
DECIPHERMED28 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMED28 
Mutations
ICGC Data PortalMED28 
TCGA Data PortalMED28 
Broad Tumor PortalMED28
OASIS PortalMED28 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMED28  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMED28
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MED28
DgiDB (Drug Gene Interaction Database)MED28
DoCM (Curated mutations)MED28 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MED28 (select a term)
intoGenMED28
NCG5 (London)MED28
Cancer3DMED28(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM610311   
Orphanet
DisGeNETMED28
MedgenMED28
Genetic Testing Registry MED28
NextProtQ9H204 [Medical]
TSGene80306
GENETestsMED28
Target ValidationMED28
Huge Navigator MED28 [HugePedia]
snp3D : Map Gene to Disease80306
BioCentury BCIQMED28
ClinGenMED28
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD80306
Chemical/Pharm GKB GenePA134935853
Clinical trialMED28
Miscellaneous
canSAR (ICR)MED28 (select the gene name)
Probes
Litterature
PubMed40 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMED28
EVEXMED28
GoPubMedMED28
iHOPMED28
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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