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PLAGL1 (Pleomorphic adenoma gene-like 1)

Written2007-08Abbas Abdollahi
Sbarro Institute for Cancer Research, Molecular Medicine, College of Science, Technology, BioLife Sciences Building, Suite 446, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namespleiomorphic adenoma gene-like 1
Alias_symbol (synonym)ZAC
LOT1
HGNC (Hugo) PLAGL1
LocusID (NCBI) 5325
Atlas_Id 41737
Location 6q24.2  [Link to chromosome band 6q24]
Location_base_pair Starts at 144261437 and ends at 144385736 bp from pter ( according to hg19-Feb_2009)  [Mapping PLAGL1.png]
Fusion genes
(updated 2016)
PHACTR2 (6q24.2) / PLAGL1 (6q24.2)PLAGL1 (6q24.2) / DYNC1H1 (14q32.31)SORBS2 (4q35.1) / PLAGL1 (6q24.2)
SZT2 (1p34.2) / PLAGL1 (6q24.2)

DNA/RNA

 
  Schematic view of the PLAGL1 gene. A. The six exons, shown in red, are 326; 72; 1443; 75; 475; 2380 bp, respectively. The introns are approximately 39; 2.6; 4.2; 12.5; 5.5 kbp in size, respectively. B. The figure shows three splice variants of PLAGL1; the exons are shown as a box.
Description The genome is about 64 kbp with six exons and five introns. The major mRNA transcript is about 4.7 kb in size.
Transcription At least three splicing variants (See Figure, above)

Protein

Description The PLAGL1 protein is a seven C2H2-type zinc finger protein. The seven zinc finger domain is located at the amino terminal region, from the amino acid residue 1 to 210. Additional features of note are proline and glutamine rich regions at the carboxyl terminal portion (residues 220 to 444). There are two nuclear localization signals at the amino terminal region.
Expression Ovary, breast, brain, liver, spleen, thymus, prostate, uterus, testis, intestine, colon, leukocytes.
Localisation Nuclear
Function The PLAGL1 protein is a candidate tumor suppressor gene and has been shown to have transactivation and DNA-binding activity and to exhibit antiproliferative activities.
Homology Homologous to the mouse and Rat plagl1 and to the human PLAG1 and PLAGL2 proteins.

Mutations

Note Mutation has not been found in the PLAGL1 coding region.

Implicated in

Note
Entity Carcinogenicity
Note Alteration of the gene expression was found to be a potential genetic event silencing the PLAGL1 gene in cancers such as breast primary tumors, ovarian primary tumors and tumor-derived cell lines, basal cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and extraskeletal myxoid chondrosarcoma (EMC). Several mechanisms have been shown to regulate the PLAGL1 gene expression, including growth factor receptor activation, epigenetic factors, maternal imprinting, and loss of heterozygosity (LOH). Allelic deletion of 6q24-q25, the PLAGL1 locus, in the tumor tissues has been shown in the cancers of ovarian, breast, HNSCC, and pheochromocytomas (PCCs).
Disease Cancer
  
Entity Transient Neonatal Diabetes (TNDM)
Note Initial reports suggested that transient neonatal diabetes mellitus (TNDM), a rare condition characterized in the patients by intrauterine growth retardation, dehydration, failure to thrive, and hyperglycemia due to a lack of normal insulin secretion, is associated with paternal uniparental disomy (UPD) of chromosome 6 (UPD 6). Later studies showed the involvement of an imprinted gene in this disease within the chromosomal region 6q24.1-q24.3 between markers D6S1699 and D6S1010. Analysis of the CpG islands in the TNDM critical region, using DNA from TNDM patients with paternal UPD 6 and normal controls, suggested PLAGL1/LOT1/ZAC1 as a candidate imprinted gene for this disease.
Disease Diabetes mellitus
  

To be noted

PLAGL1 has been implicated in embryonic development. The gene is variably expressed in different tissues and stages during development. Inactivation of this maternally repressed gene resulted in intrauterine growth restriction, altered bone formation, and neonatal lethality.

Bibliography

LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions.
Abdollahi A
Journal of cellular physiology. 2007 ; 210 (1) : 16-25.
PMID 17063461
 
LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer.
Abdollahi A, Pisarcik D, Roberts D, Weinstein J, Cairns P, Hamilton TC
The Journal of biological chemistry. 2003 ; 278 (8) : 6041-6049.
PMID 12473647
 
A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC.
Arima T, Drewell RA, Oshimura M, Wake N, Surani MA
Genomics. 2000 ; 67 (3) : 248-255.
PMID 10936046
 
ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.
Arima T, Kamikihara T, Hayashida T, Kato K, Inoue T, Shirayoshi Y, Oshimura M, Soejima H, Mukai T, Wake N
Nucleic acids research. 2005 ; 33 (8) : 2650-2660.
PMID 15888726
 
Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region during oogenesis.
Arima T, Wake N
Cytogenetic and genome research. 2006 ; 113 (1-4) : 247-252.
PMID 16575187
 
The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice.
Arima T, Yamasaki K, John RM, Kato K, Sakumi K, Nakabeppu Y, Wake N, Kono T
Genomics. 2006 ; 88 (5) : 650-658.
PMID 16928428
 
Peroxisome proliferator-activated receptor gamma is a Zac target gene mediating Zac antiproliferation.
Barz T, Hoffmann A, Panhuysen M, Spengler D
Cancer research. 2006 ; 66 (24) : 11975-11982.
PMID 17178896
 
The candidate tumor suppressor gene ZAC is involved in keratinocyte differentiation and its expression is lost in basal cell carcinomas.
Basyuk E, Coulon V, Le Digarcher A, Coisy-Quivy M, Moles JP, Gandarillas A, Journot L
Molecular cancer research : MCR. 2005 ; 3 (9) : 483-492.
PMID 16179495
 
Alternative splicing of the imprinted candidate tumor suppressor gene ZAC regulates its antiproliferative and DNA binding activities.
Bilanges B, Varrault A, Mazumdar A, Pantaloni C, Hoffmann A, Bockaert J, Spengler D, Journot L
Oncogene. 2001 ; 20 (10) : 1246-1253.
PMID 11313869
 
Developmental expression of the cell cycle and apoptosis controlling gene, Lot1, in the rat cerebellum and in cultures of cerebellar granule cells.
Ciani E, Frenquelli M, Contestabile A
Brain research. Developmental brain research. 2003 ; 142 (2) : 193-202.
PMID 12711370
 
Cyclic AMP-mediated regulation of transcription factor Lot1 expression in cerebellar granule cells.
Contestabile A, Fila T, Bartesaghi R, Ciani E
The Journal of biological chemistry. 2005 ; 280 (39) : 33541-33551.
PMID 16061485
 
Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer.
Cvetkovic D, Pisarcik D, Lee C, Hamilton TC, Abdollahi A
Gynecologic oncology. 2004 ; 95 (3) : 449-455.
PMID 15581945
 
Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice.
Gillardon F, Hata R, Hossmann KA
Brain research. Molecular brain research. 1998 ; 61 (1-2) : 207-210.
PMID 9795221
 
The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities.
Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML
Cancer research. 2002 ; 62 (5) : 1510-1517.
PMID 11888928
 
Multitasking C2H2 zinc fingers link Zac DNA binding to coordinated regulation of p300-histone acetyltransferase activity.
Hoffmann A, Barz T, Spengler D
Molecular and cellular biology. 2006 ; 26 (14) : 5544-5557.
PMID 16809786
 
Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1.
Huang SM, Schönthal AH, Stallcup MR
Oncogene. 2001 ; 20 (17) : 2134-2143.
PMID 11360197
 
Mouse Zac1, a transcriptional coactivator and repressor for nuclear receptors.
Huang SM, Stallcup MR
Molecular and cellular biology. 2000 ; 20 (5) : 1855-1867.
PMID 10669760
 
Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.
Kamikihara T, Arima T, Kato K, Matsuda T, Kato H, Douchi T, Nagata Y, Nakao M, Wake N
International journal of cancer. Journal international du cancer. 2005 ; 115 (5) : 690-700.
PMID 15751035
 
The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes.
Kamiya M, Judson H, Okazaki Y, Kusakabe M, Muramatsu M, Takada S, Takagi N, Arima T, Wake N, Kamimura K, Satomura K, Hermann R, Bonthron DT, Hayashizaki Y
Human molecular genetics. 2000 ; 9 (3) : 453-460.
PMID 10655556
 
Transcriptional activation capacity of the novel PLAG family of zinc finger proteins.
Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ
The Journal of biological chemistry. 1998 ; 273 (36) : 23026-23032.
PMID 9722527
 
Loss of expression of ZAC/LOT1 in squamous cell carcinomas of head and neck.
Koy S, Hauses M, Appelt H, Friedrich K, Schackert HK, Eckelt U
Head & neck. 2004 ; 26 (4) : 338-344.
PMID 15054737
 
Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.
Mackay DJ, Coupe AM, Shield JP, Storr JN, Temple IK, Robinson DO
Human genetics. 2002 ; 110 (2) : 139-144.
PMID 11935319
 
The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas.
Pagotto U, Arzberger T, Theodoropoulou M, Grübler Y, Pantaloni C, Saeger W, Losa M, Journot L, Stalla GK, Spengler D
Cancer research. 2000 ; 60 (24) : 6794-6799.
PMID 11156367
 
Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines.
Piras G, El Kharroubi A, Kozlov S, Escalante-Alcalde D, Hernandez L, Copeland NG, Gilbert DJ, Jenkins NA, Stewart CL
Molecular and cellular biology. 2000 ; 20 (9) : 3308-3315.
PMID 10757814
 
The PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors.
Poulin H, Labelle Y
Cancer letters. 2005 ; 227 (2) : 185-191.
PMID 16112421
 
The mouse Zac1 locus: basis for imprinting and comparison with human ZAC.
Smith RJ, Arnaud P, Konfortova G, Dean WL, Beechey CV, Kelsey G
Gene. 2002 ; 292 (1-2) : 101-112.
PMID 12119104
 
Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.
Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L
The EMBO journal. 1997 ; 16 (10) : 2814-2825.
PMID 9184226
 
Expression pattern of Zac1 mouse gene, a new zinc-finger protein that regulates apoptosis and cellular cycle arrest, in both adult brain and along development.
Valente T, Auladell C
Mechanisms of development. 2001 ; 108 (1-2) : 207-211.
PMID 11578877
 
Zac1 is up-regulated in neural cells of the limbic system of mouse brain following seizures that provoke strong cell activation.
Valente T, Domínguez MI, Bellmann A, Journot L, Ferrer I, Auladell C
Neuroscience. 2004 ; 128 (2) : 323-336.
PMID 15350644
 
Zac1 is expressed in progenitor/stem cells of the neuroectoderm and mesoderm during embryogenesis: differential phenotype of the Zac1-expressing cells during development.
Valente T, Junyent F, Auladell C
Developmental dynamics : an official publication of the American Association of Anatomists. 2005 ; 233 (2) : 667-679.
PMID 15844099
 
Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters.
Valleley EM, Cordery SF, Bonthron DT
Human molecular genetics. 2007 ; 16 (8) : 972-981.
PMID 17341487
 
Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth.
Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C, Severac D, Chotard L, Kahli M, Le Digarcher A, Pavlidis P, Journot L
Developmental cell. 2006 ; 11 (5) : 711-722.
PMID 17084362
 
DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth.
Wu C, Daniels RW, Diantonio A
Neural development. 2007 ; 2 : page 16.
PMID 17697379
 
Physical and functional interactions of human papillomavirus E2 protein with nuclear receptor coactivators.
Wu MH, Huang CJ, Liu ST, Liu PY, Ho CL, Huang SM
Biochemical and biophysical research communications. 2007 ; 356 (3) : 523-528.
PMID 17376404
 

Citation

This paper should be referenced as such :
Abdollahi, A
PLAGL1 (pleomorphic adenoma gene-like 1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):127-129.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PLAGL1ID41737ch6q24.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Soft Tissues: Lipoblastoma


External links

Nomenclature
HGNC (Hugo)PLAGL1   9046
LRG (Locus Reference Genomic)LRG_1101
Cards
AtlasPLAGL1ID41737ch6q24
Entrez_Gene (NCBI)PLAGL1  5325  PLAG1 like zinc finger 1
AliasesLOT1; ZAC; ZAC1
GeneCards (Weizmann)PLAGL1
Ensembl hg19 (Hinxton)ENSG00000118495 [Gene_View]  chr6:144261437-144385736 [Contig_View]  PLAGL1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000118495 [Gene_View]  chr6:144261437-144385736 [Contig_View]  PLAGL1 [Vega]
ICGC DataPortalENSG00000118495
TCGA cBioPortalPLAGL1
AceView (NCBI)PLAGL1
Genatlas (Paris)PLAGL1
WikiGenes5325
SOURCE (Princeton)PLAGL1
Genetics Home Reference (NIH)PLAGL1
Genomic and cartography
GoldenPath hg19 (UCSC)PLAGL1  -     chr6:144261437-144385736 -  6q24-q25   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PLAGL1  -     6q24-q25   [Description]    (hg38-Dec_2013)
EnsemblPLAGL1 - 6q24-q25 [CytoView hg19]  PLAGL1 - 6q24-q25 [CytoView hg38]
Mapping of homologs : NCBIPLAGL1 [Mapview hg19]  PLAGL1 [Mapview hg38]
OMIM601410   603044   
Gene and transcription
Genbank (Entrez)AI741398 AJ006354 AJ303119 AJ311395 AK091707
RefSeq transcript (Entrez)NM_001080951 NM_001080952 NM_001080953 NM_001080954 NM_001080955 NM_001080956 NM_001289037 NM_001289038 NM_001289039 NM_001289040 NM_001289041 NM_001289042 NM_001289043 NM_001289044 NM_001289045 NM_001289046 NM_001289047 NM_001289048 NM_001289049 NM_001317156 NM_001317157 NM_001317158 NM_001317159 NM_001317160 NM_001317161 NM_001317162 NM_002656 NM_006718
RefSeq genomic (Entrez)NC_000006 NC_018917 NG_009384 NT_025741 NW_004929328
Consensus coding sequences : CCDS (NCBI)PLAGL1
Cluster EST : UnigeneHs.743225 [ NCBI ]
CGAP (NCI)Hs.743225
Alternative Splicing GalleryENSG00000118495
Gene ExpressionPLAGL1 [ NCBI-GEO ]   PLAGL1 [ EBI - ARRAY_EXPRESS ]   PLAGL1 [ SEEK ]   PLAGL1 [ MEM ]
Gene Expression Viewer (FireBrowse)PLAGL1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5325
GTEX Portal (Tissue expression)PLAGL1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UM63   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UM63  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UM63
Splice isoforms : SwissVarQ9UM63
PhosPhoSitePlusQ9UM63
Domaine pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Domain families : Pfam (Sanger)zf-C2H2 (PF00096)   
Domain families : Pfam (NCBI)pfam00096   
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
Conserved Domain (NCBI)PLAGL1
DMDM Disease mutations5325
Blocks (Seattle)PLAGL1
SuperfamilyQ9UM63
Human Protein AtlasENSG00000118495
Peptide AtlasQ9UM63
HPRD16010
IPIIPI00645881   IPI00220818   IPI01009516   IPI00375897   
Protein Interaction databases
DIP (DOE-UCLA)Q9UM63
IntAct (EBI)Q9UM63
FunCoupENSG00000118495
BioGRIDPLAGL1
STRING (EMBL)PLAGL1
ZODIACPLAGL1
Ontologies - Pathways
QuickGOQ9UM63
Ontology : AmiGORNA polymerase II regulatory region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding  DNA binding  nucleus  nucleoplasm  nucleoplasm  Golgi apparatus  transcription from RNA polymerase II promoter  apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  cell differentiation  skeletal muscle cell differentiation  intracellular membrane-bounded organelle  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
Ontology : EGO-EBIRNA polymerase II regulatory region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding  DNA binding  nucleus  nucleoplasm  nucleoplasm  Golgi apparatus  transcription from RNA polymerase II promoter  apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  cell differentiation  skeletal muscle cell differentiation  intracellular membrane-bounded organelle  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  
NDEx NetworkPLAGL1
Atlas of Cancer Signalling NetworkPLAGL1
Wikipedia pathwaysPLAGL1
Orthology - Evolution
OrthoDB5325
GeneTree (enSembl)ENSG00000118495
Phylogenetic Trees/Animal Genes : TreeFamPLAGL1
HOVERGENQ9UM63
HOGENOMQ9UM63
Homologs : HomoloGenePLAGL1
Homology/Alignments : Family Browser (UCSC)PLAGL1
Gene fusions - Rearrangements
Fusion : MitelmanPHACTR2/PLAGL1 [6q24.2/6q24.2]  [t(6;6)(q24;q24)]  
Fusion: TCGAPHACTR2 6q24.2 PLAGL1 6q24.2 HNSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPLAGL1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PLAGL1
dbVarPLAGL1
ClinVarPLAGL1
1000_GenomesPLAGL1 
Exome Variant ServerPLAGL1
ExAC (Exome Aggregation Consortium)PLAGL1 (select the gene name)
Genetic variants : HAPMAP5325
Genomic Variants (DGV)PLAGL1 [DGVbeta]
DECIPHER (Syndromes)6:144261437-144385736  ENSG00000118495
CONAN: Copy Number AnalysisPLAGL1 
Mutations
ICGC Data PortalPLAGL1 
TCGA Data PortalPLAGL1 
Broad Tumor PortalPLAGL1
OASIS PortalPLAGL1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPLAGL1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPLAGL1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PLAGL1
DgiDB (Drug Gene Interaction Database)PLAGL1
DoCM (Curated mutations)PLAGL1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PLAGL1 (select a term)
intoGenPLAGL1
NCG5 (London)PLAGL1
Cancer3DPLAGL1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601410    603044   
Orphanet12815    14459   
MedgenPLAGL1
Genetic Testing Registry PLAGL1
NextProtQ9UM63 [Medical]
TSGene5325
GENETestsPLAGL1
Huge Navigator PLAGL1 [HugePedia]
snp3D : Map Gene to Disease5325
BioCentury BCIQPLAGL1
ClinGenPLAGL1 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5325
Chemical/Pharm GKB GenePA33379
Clinical trialPLAGL1
Miscellaneous
canSAR (ICR)PLAGL1 (select the gene name)
Probes
Litterature
PubMed76 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePLAGL1
EVEXPLAGL1
GoPubMedPLAGL1
iHOPPLAGL1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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