PLAGL1 (Pleomorphic adenoma gene-like 1)

Identity

Other names	DKFZp781P1017
	LOT1
	MGC126275
	MGC126276
	ZAC
	ZAC1
HGNC	PLAGL1
Location	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

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.

External links

	Nomenclature
HGNC	PLAGL1   9046
Entrez_Gene	PLAGL1  5325  pleiomorphic adenoma gene-like 1
	Cards
Atlas	PLAGL1ID41737ch6q24
GeneCards	PLAGL1
Ensembl	PLAGL1 [Search_View]   ENSG00000118495 [Gene_View]
Genatlas	PLAGL1
GeneLynx	PLAGL1
eGenome	PLAGL1
euGene	5325
	Genomic and cartography
GoldenPath	PLAGL1  -  6q24.2   chr6:144303130-144427428 -  6q24-q25   [Description]    (hg18-Mar_2006)
Ensembl	PLAGL1 - 6q24-q25 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	PLAGL1
	Gene and transcription
Genbank	AI741398 [ ENTREZ ]
Genbank	AJ006354 [ ENTREZ ]
Genbank	AJ303119 [ ENTREZ ]
Genbank	AJ311395 [ ENTREZ ]
Genbank	AK091707 [ ENTREZ ]
RefSeq	NM_001080951 [ SRS ]    NM_001080951 [ ENTREZ ]
RefSeq	NM_001080952 [ SRS ]    NM_001080952 [ ENTREZ ]
RefSeq	NM_001080953 [ SRS ]    NM_001080953 [ ENTREZ ]
RefSeq	NM_001080954 [ SRS ]    NM_001080954 [ ENTREZ ]
RefSeq	NM_001080955 [ SRS ]    NM_001080955 [ ENTREZ ]
RefSeq	NM_001080956 [ SRS ]    NM_001080956 [ ENTREZ ]
RefSeq	NM_002656 [ SRS ]    NM_002656 [ ENTREZ ]
RefSeq	NM_006718 [ SRS ]    NM_006718 [ ENTREZ ]
RefSeq	AC_000049 [ SRS ]    AC_000049 [ ENTREZ ]
RefSeq	AC_000138 [ SRS ]    AC_000138 [ ENTREZ ]
RefSeq	NC_000006 [ SRS ]    NC_000006 [ ENTREZ ]
RefSeq	NT_025741 [ SRS ]    NT_025741 [ ENTREZ ]
RefSeq	NW_001838990 [ SRS ]    NW_001838990 [ ENTREZ ]
RefSeq	NW_923184 [ SRS ]    NW_923184 [ ENTREZ ]
AceView	PLAGL1 AceView - NCBI
Unigene	Hs.444975 [ SRS ]    Hs.444975 [ NCBI ]     HS444975 [ spliceNest ]
Fast-db	16730 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q5TFH3 [ SRS]    Q5TFH3 [ EXPASY ]     Q5TFH3 [ INTERPRO ]     Q5TFH3 [ UNIPROT ]
Prosite	PS00028 ZINC_FINGER_C2H2_1 [ SRS ]    PS00028 ZINC_FINGER_C2H2_1 [ Expasy ]
Prosite	PS50157 ZINC_FINGER_C2H2_2 [ SRS ]    PS50157 ZINC_FINGER_C2H2_2 [ Expasy ]
Interpro	IPR007087 Znf_C2H2 [ SRS ]    IPR007087 Znf_C2H2 [ EBI ]
Interpro	IPR015880 Znf_C2H2-like [ SRS ]    IPR015880 Znf_C2H2-like [ EBI ]
Interpro	IPR013087 Znf_C2H2/integrase_DNA-bd [ SRS ]    IPR013087 Znf_C2H2/integrase_DNA-bd [ EBI ]
CluSTr	Q5TFH3
Pfam	PF00096 zf-C2H2 [ SRS ]    PF00096 zf-C2H2 [ Sanger ]    pfam00096 [ NCBI-CDD ]
Smart	SM00355 ZnF_C2H2 [EMBL]
Prodom	PD000003 Znf_C2H2[INRA-Toulouse]
Prodom	Q5TFH3 Q5TFH3_HUMAN [ Domain structure ]   Q5TFH3 Q5TFH3_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	Q5TFH3
HPRD	16010
	Protein Interaction databases
DIP	Q5TFH3
IntAct	Q5TFH3
	Polymorphism : SNP, mutations, diseases
OMIM	601410;603044    [ map ]
GENECLINICS	601410;603044
SNP	PLAGL1 [dbSNP-NCBI]
SNP	NM_001080951 [SNP-NCI]
SNP	NM_001080952 [SNP-NCI]
SNP	NM_001080953 [SNP-NCI]
SNP	NM_001080954 [SNP-NCI]
SNP	NM_001080955 [SNP-NCI]
SNP	NM_001080956 [SNP-NCI]
SNP	NM_002656 [SNP-NCI]
SNP	NM_006718 [SNP-NCI]
SNP	PLAGL1 [GeneSNPs - Utah]  PLAGL1] [HGBASE - SRS]
HAPMAP	PLAGL1 [HAPMAP]
HGMD	PLAGL1
	General knowledge
Family Browser	PLAGL1 [UCSC Family Browser]
SOURCE	NM_001080951
SOURCE	NM_001080952
SOURCE	NM_001080953
SOURCE	NM_001080954
SOURCE	NM_001080955
SOURCE	NM_001080956
SOURCE	NM_002656
SOURCE	NM_006718
SMD	Hs.444975
SAGE	Hs.444975
GO	nucleic acid binding [Amigo]  nucleic acid binding
GO	DNA binding [Amigo]  DNA binding
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	transcription [Amigo]  transcription
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	induction of apoptosis [Amigo]  induction of apoptosis
GO	cell cycle arrest [Amigo]  cell cycle arrest
GO	zinc ion binding [Amigo]  zinc ion binding
GO	positive regulation of transcription from RNA polymerase II promoter [Amigo]  positive regulation of transcription from RNA polymerase II promoter
GO	metal ion binding [Amigo]  metal ion binding
PubGene	PLAGL1
TreeFam	PLAGL1
CTD	5325 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	PLAGL1 Related clones (RZPD - Berlin)
	PubMed
PubMed	30 Pubmed reference(s) in LocusLink

Bibliography

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PMID 9150364

Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells.

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Cancer research. 1997 ; 57 (10) : 2029-2034.

PMID 9158001

Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.

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Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice.

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PMID 9795221

Transcriptional activation capacity of the novel PLAG family of zinc finger proteins.

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The Journal of biological chemistry. 1998 ; 273 (36) : 23026-23032.

PMID 9722527

hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer.

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PMID 9671765

LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor receptor ligands and encodes a nuclear zinc-finger protein.

Abdollahi A, Bao R, Hamilton TC

Oncogene. 1999 ; 18 (47) : 6477-6487.

PMID 10597250

Loss of expression of the candidate tumor suppressor gene ZAC in breast cancer cell lines and primary tumors.

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PMID 10435621

Inhibition of Zac1, a new gene differentially expressed in the anterior pituitary, increases cell proliferation.

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Endocrinology. 1999 ; 140 (2) : 987-996.

PMID 9927333

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

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

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

The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas.

Pagotto U, Arzberger T, Theodoropoulou M, Grˆşbler 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

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

Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1.

Huang SM, Schˆnthal AH, Stallcup MR

Oncogene. 2001 ; 20 (17) : 2134-2143.

PMID 11360197

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

Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus.

Varrault A, Bilanges B, Mackay DJ, Basyuk E, Ahr B, Fernandez C, Robinson DO, Bockaert J, Journot L

The Journal of biological chemistry. 2001 ; 276 (22) : 18653-18656.

PMID 11297535

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

Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.

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Human genetics. 2002 ; 110 (2) : 139-144.

PMID 11935319

The mouse Zac1 locus: basis for imprinting and comparison with human ZAC.

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PMID 12119104

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

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

Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding.

Hoffmann A, Ciani E, Boeckardt J, Holsboer F, Journot L, Spengler D

Molecular and cellular biology. 2003 ; 23 (3) : 988-1003.

PMID 12529403

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

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

Zac1 is up-regulated in neural cells of the limbic system of mouse brain following seizures that provoke strong cell activation.

Valente T, Domˆ‚nguez MI, Bellmann A, Journot L, Ferrer I, Auladell C

Neuroscience. 2004 ; 128 (2) : 323-336.

PMID 15350644

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

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

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

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 PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors.

Poulin H, Labelle Y

Cancer letters. 2005 ; 227 (2) : 185-191.

PMID 16112421

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

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

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

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

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

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

LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions.

Abdollahi A

Journal of cellular physiology. 2007 ; 210 (1) : 16-25.

PMID 17063461

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

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

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

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Contributor(s)

Written	08-2007	Abbas Abdollahi
		Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, BioLife Sciences Building, Suite 446, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA

Citation

This paper should be referenced as such :

Abdollahi A . PLAGL1 (Pleomorphic adenoma gene-like 1). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PLAGL1ID41737ch6q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:16:25 2008