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  6. Zinc finger protein PLAGL1

Tbio Zinc finger protein PLAGL1

Shows weak transcriptional activatory activity. Transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide.

This gene encodes a C2H2 zinc finger protein that functions as a suppressor of cell growth. This gene is often deleted or methylated and silenced in cancer cells. In addition, overexpression of this gene during fetal development is thought to be the causal factor for transient neonatal diabetes mellitus (TNDM). Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding two different protein isoforms. The P1 downstream promoter of this gene is imprinted, with preferential expression from the paternal allele in many tissues. [provided by RefSeq, Nov 2015]

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Property Summary

NCBI Gene PubMed Count 74
PubMed Score 111.02
PubTator Score 155.60

Knowledge Summary

Patent

No data available

TINX Plot

  Disease (4)

Expression

  Differential Expression (24)

Disease log2 FC p
malignant mesothelioma -4.900 5.1e-08
glioblastoma -1.400 4.5e-03
atypical teratoid/rhabdoid tumor 2.800 4.8e-05
Duchenne muscular dystrophy 1.951 2.8e-06
autosomal dominant Emery-Dreifuss muscul... 1.674 1.1e-02
juvenile dermatomyositis 2.040 2.0e-11
non-small cell lung cancer -1.251 9.2e-12
intraductal papillary-mucinous adenoma (... -1.400 1.9e-02
intraductal papillary-mucinous neoplasm ... -2.300 6.3e-03
colon cancer -2.300 3.6e-03
lung cancer -2.600 6.5e-06
active ulcerative colitis -1.434 3.6e-02
breast carcinoma -1.900 2.7e-21
aldosterone-producing adenoma -1.527 9.6e-03
invasive ductal carcinoma -2.600 6.5e-04
Breast cancer -2.900 7.1e-12
Polycystic Ovary Syndrome 1.050 1.3e-02
lung carcinoma -2.400 4.5e-40
spina bifida -1.886 2.9e-02
Pick disease 1.100 7.1e-04
ductal carcinoma in situ -1.800 1.5e-03
ovarian cancer -3.900 2.0e-08
pituitary cancer -6.300 1.6e-12
dermatomyositis 1.200 3.7e-03

Synonym

Accession Q9UM63 B2RBA4 B2RCM8 E1P595 E1P597 O76019 Q7Z3V8 Q92981 Q96JR9 Q9UIZ0
Symbols ZAC
LOT1
ZAC1

Gene

PLAGL1

PANTHER Protein Class (3)

  Ortholog (1)

Species Source Disease
Chimp OMA EggNOG

 UniProt Keyword (13)

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 GO Function (4)

 GO Component (4)

 GO Process (6)

 Compartment GO Term (24)

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 MGI Phenotype (10)

 GWAS Trait (1)

 HCA RNA Cell Line (56)

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Pathway (8)

Gene RIF (42)

PMID Text
26851016 High PLAGL1 mRNA and protein levels were associated with Clear Cell Renal Cell Carcinoma.
26134521 Results suggest that dysregulation of PLAGL1 expression may be involved in the progression of colorectal cancer (CRC) but the patient survival data do not confirm applicability of the PLAGL1 expression level as a prognostic factor in CRC.
25091631 DNA deletion and promoter hyper-methylation both contribute to the down-regulation of PLAGL1 in gastric adenocarcinoma
24993786 Fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta.
24316753 There is positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03).
24260468 research identified a specific CpG site where determination of the methylation status was associated with both metastasis-free and overall survival in undifferentiated sarcoma.
24098585 ZAC1 and SSTR2 are down-regulated in non-functioning pituitary adenomas but not in somatotropinomas.
23415968 Paternal methylation aberrations at imprinting control regions of DLK1-GTL2, MEST (PEG1), and ZAC (PLAGL1) and global methylation levels are not associated with idiopathic recurrent spontaneous miscarriages.
23333304 HIV-1 Vif downregulates the expression of pleiomorphic adenoma gene-like 1 (PLAGL1) in Vif-expression T cells
23295672 The imprinted PLAGL1 domain is flanked by CTCF-binding sites conserved between species in both expressing and non-expressing cells.
23153226 Based on these findings we conclude that the imprinted gene expression of KCNQ1OT1, CDKN1C, H19, and PLAGL1 are conserved between human and bovine
22784302 detected a synonymous variation in the protein-coding exon-2 of PLAGL1 in isolated VSD patients. It is possible that the etiology of isolated VSD might not be directly linked with this mutation
22227369 This work indicates that Zac1 functions are regulated, at least in part, via non-covalent interactions with SUMO-1 for the induction of p21, which is important for the modulation of apoptosis.
22001409 Zac1 is able to interact directly with the Sp1-responsive element in the p21(WAF1/Cip1) gene promoter.
21872827 Our study suggests the involvement of the imprinted ZAC gene in the pathogenesis of pheochromocytoma.
21305342 The specific expression of ZAC in the human fetal beta-cells supports it as the gene involved in transient neonatal diabetes mellitus
20518900 ZAC1 may have a role in tumorigenesis of von Hippel-Lindau associated central nervous system hemangioblastoma.
20487506 Observational study and genome-wide association study of gene-disease association. (HuGE Navigator)
20363751 ZAC1 is a novel and previously unknown regulator of cardiomyocyte Glut4 expression and glucose uptake; MEF2 is a regulator of ZAC1 expression in response to induction of hypertrophy
20175198 Data indicates that downregulation of ZAC occurs in diffuse large B-cell lymphoma. As ZAC expression in normal B lymphocytes is derived from promoter P2, in DLBCL we analyzed both promoter P1 and P2 for gene expression, LOH and abnormal methylation.
19694203 Our results do not indicate a relevant role of mutations in LOT1(ZAC1/PLAGL1) in the etiology of Silver-Russell Syndrome.
19423711 The zinc-finger protein ZAC1 is up-regulated under hypertonic stress and negatively regulates expression of sorbitol dehydrogenase, allowing for accumulation of sorbitol as a compatible organic osmolyte.
19155788 No evidence was found that polymorphisms in ZAC1 might influence anthropometric, biochemical or clinical parameters in French individuals.
19155788 Observational study of gene-disease association. (HuGE Navigator)
18663001 Here it is shown that Zac1, together with the coactivators p300 and PCAF, recruit to the p21(Cip1) promoter during the differentiation of embryonic stem cells into neurons.
18644983 Zac1 might be involved in regulating the p21(WAF1/Cip1) gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.
17805016 Absence of unmethylated ZAC1 sequence was highly concurrent with ZAC1 region LOH or 6q loss and with lack of ZAC1 expression, suggesting preferential loss of nonimprinted, expressed ZAC1 allele in capillary hemangioblastoma.
17341487 Tissue-specific imprinting of PLAGL1 gene results from variable use of monoallelic and biallelic promoters.
17178896 a functional relationship between Zac and PPARgamma that could be relevant to the understanding of tumorigenesis and diabetes as well.
16928428 a transgene carrying the human HYMAI/PLAGL1 differentially methylated region was methylated in the correct parent-origin-specific manner in mice and this was sufficient to confer imprinted expression from the transgene
16873690 Observational study of gene-disease association. (HuGE Navigator)
16809786 coordinated binding of Zac zinc fingers and C terminus to p300 regulates HAT function by increasing histone and acetyl coenzyme A affinities and catalytic activity
16733217 Using the ZAC1-specific marker located at 6q24-25, LOH or allelic imbalance was observed.
16179495 Loss of ZAC expression is associated with basal cell carcinomas of skin.
16112421 Down-regulation of PLAGL1 is associated with extraskeletal myxoid chondrosarcoma tumors
15888726 Mutations in ZAC may contribute to Beckwith-Wiedemann syndrome.
15592663 Mutated in multiple congenital abnormalities including neonatasl diabstes, hypoplastic pasnscreas, intestinal atresia and gallbladdre dysplasia.
15581945 The altered expression and LOH of the LOT1 locus support the gene's potential role in the pathogenesis of ovarian cancer and possibly in other types of cancer.
12529403 Zac contains transactivation activities that are differentially controlled by DNA binding.
12473647 This candidate tumor suppressor gene, located at chromosome 6q24-25, is epigenetically regulated in cancer
11935319 genetically imprinted in neonatal diabetes
10655556 PLAGL1 gene is imprinted, with preferential expression from the paternal allele in many tissues.

AA Sequence 

MATFPCQLCGKTFLTLEKFTIHNYSHSRERPYKCVQPDCGKAFVSRYKLMRHMATHSPQKSHQCAHCEKT      1 - 70
FNRKDHLKNHLQTHDPNKMAFGCEECGKKYNTMLGYKRHLALHAASSGDLTCGVCALELGSTEVLLDHLK     71 - 140
AHAEEKPPSGTKEKKHQCDHCERCFYTRKDVRRHLVVHTGCKDFLCQFCAQRFGRKDHLTRHTKKTHSQE    141 - 210
LMKESLQTGDLLSTFHTISPSFQLKAAALPPFPLGASAQNGLASSLPAEVHSLTLSPPEQAAQPMQPLPE    211 - 280
SLASLHPSVSPGSPPPPLPNHKYNTTSTSYSPLASLPLKADTKGFCNISLFEDLPLQEPQSPQKLNPGFD    281 - 350
LAKGNAGKVNLPKELPADAVNLTIPASLDLSPLLGFWQLPPPATQNTFGNSTLALGPGESLPHRLSCLGQ    351 - 420
QQQEPPLAMGTVSLGQLPLPPIPHVFSAGTGSAILPHFHHAFR                               421 - 463
//

Text Mined References (76)

PMID Year Title
26851016 2016 PLAGL1 (ZAC1/LOT1) Expression in Clear Cell Renal Cell Carcinoma: Correlations with Disease Progression and Unfavorable Prognosis.
26134521 2015 Altered expression of the PLAGL1 (ZAC1/LOT1) gene in colorectal cancer: Correlations to the clinicopathological parameters.
25091631 2014 Both gene deletion and promoter hyper-methylation contribute to the down-regulation of ZAC/PLAGL1 gene in gastric adenocarcinomas: a case control study.
24993786 2014 Altered expression of the imprinted transcription factor PLAGL1 deregulates a network of genes in the human IUGR placenta.
24316753 2014 Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort.
24260468 2013 Prognostic value of PLAGL1-specific CpG site methylation in soft-tissue sarcomas.
24098585 2013 ZAC1 and SSTR2 are downregulated in non-functioning pituitary adenomas but not in somatotropinomas.
23630160 2013 Zac1 regulates astroglial differentiation of neural stem cells through Socs3.
23415968 2013 Methylation status of imprinted genes DLK1-GTL2, MEST (PEG1), ZAC (PLAGL1), and LINE-1 elements in spermatozoa of normozoospermic men, unlike H19 imprinting control regions, is not associated with idiopathic recurrent spontaneous miscarriages.
23295672 2013 Imprinting at the PLAGL1 domain is contained within a 70-kb CTCF/cohesin-mediated non-allelic chromatin loop.
23153226 2012 Expression of KCNQ1OT1, CDKN1C, H19, and PLAGL1 and the methylation patterns at the KvDMR1 and H19/IGF2 imprinting control regions is conserved between human and bovine.
22784302 2012 A novel variation of PLAGL1 in Chinese patients with isolated ventricular septal defect.
22659247 2012 Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway.
22227369 2012 A non-covalent interaction between small ubiquitin-like modifier-1 and Zac1 regulates Zac1 cellular functions.
22001409 2011 Zac1, an Sp1-like protein, regulates human p21(WAF1/Cip1) gene expression in HeLa cells.
21872827 2011 Tumor suppressor gene ZAC/PLAGL1: altered expression and loss of the nonimprinted allele in pheochromocytomas.
21864583 2011 Zac1 functional interactions mediate AP-1 transcriptional activity.
21546906 2011 Zac1 is a histone acetylation-regulated NF-?B suppressor that mediates histone deacetylase inhibitor-induced apoptosis.
21305342 2011 Differential expression pattern of ZAC in developing mouse and human pancreas.
20518900 2010 Molecularly genetic analysis of von Hippel-Lindau associated central nervous system hemangioblastoma.
20487506 2010 A whole genome association study of mother-to-child transmission of HIV in Malawi.
20363751 2010 Regulation of cardiomyocyte Glut4 expression by ZAC1.
20175198 2010 Loss of expression of ZAC/PLAGL1 in diffuse large B-cell lymphoma is independent of promoter hypermethylation.
20117169 2010 ZAC1 target genes and pituitary tumorigenesis.
20097304 2010 Modulation of the Zac1's transactivation and coactivation functions via PML and Daxx within distinct subcellular localizations.
19694203 2009 LOT1 (ZAC1/PLAGL1) as member of an imprinted gene network does not harbor Silver-Russell specific variants.
19637311 2009 Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly.
19423711 2009 ZAC1 is up-regulated by hypertonicity and decreases sorbitol dehydrogenase expression, allowing accumulation of sorbitol in kidney cells.
19155788 2009 Study of the genetic variability of ZAC1 (PLAGL1) in French population-based samples.
19092779 2009 Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome.
18663001 2008 A new coactivator function for Zac1's C2H2 zinc finger DNA-binding domain in selectively controlling PCAF activity.
18644983 2008 Modulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells.
18299245 2008 Human Spot 14 protein is a p53-dependent transcriptional coactivator via the recruitment of thyroid receptor and Zac1.
17974005 2007 The full-ORF clone resource of the German cDNA Consortium.
17805016 2007 Preferential loss of the nonimprinted allele for the ZAC1 tumor suppressor gene in human capillary hemangioblastoma.
17552003 2007 Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil.
17341487 2007 Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters.
17178896 2006 Peroxisome proliferator-activated receptor gamma is a Zac target gene mediating Zac antiproliferation.
17109628 2007 Importin alpha1 is involved in the nuclear localization of Zac1 and the induction of p21WAF1/CIP1 by Zac1.
17084362 2006 Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth.
17063461 2007 LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions.
16928428 2006 The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice.
16873690 2006 Assessment of the role of common genetic variation in the transient neonatal diabetes mellitus (TNDM) region in type 2 diabetes: a comparative genomic and tagging single nucleotide polymorphism approach.
16809786 2006 Multitasking C2H2 zinc fingers link Zac DNA binding to coordinated regulation of p300-histone acetyltransferase activity.
16733217 2006 Frequent loss of heterozygosity at 6q in pheochromocytoma.
16344560 2006 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.
16179495 2005 The candidate tumor suppressor gene ZAC is involved in keratinocyte differentiation and its expression is lost in basal cell carcinomas.
16112421 2005 The PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors.
15888726 2005 ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.
15751035 2005 Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.
15592663 2004 Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.
15581945 2004 Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer.
15560839 2004 Molecular analyses of the candidate tumor suppressor gene, PLAGL1, in benign and malignant salivary gland tumors.
15489334 2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15286800 2004 Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.
15231748 2004 Functional proteomics mapping of a human signaling pathway.
15054737 2004 Loss of expression of ZAC/LOT1 in squamous cell carcinomas of head and neck.
14702039 2004 Complete sequencing and characterization of 21,243 full-length human cDNAs.
14574404 2003 The DNA sequence and analysis of human chromosome 6.
12529403 2003 Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
12473647 2003 LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer.
11935319 2002 Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.
11896574 2002 A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1.
11448939 2001 A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus.
11360197 2001 Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1.
11313869 2001 Alternative splicing of the imprinted candidate tumor suppressor gene ZAC regulates its antiproliferative and DNA binding activities.
10655556 2000 The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes.
10597250 1999 LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor receptor ligands and encodes a nuclear zinc-finger protein.
9722527 1998 Transcriptional activation capacity of the novel PLAG family of zinc finger proteins.
9671765 1998 hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer.
9184226 1997 Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.
9158001 1997 Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells.
9150364 1997 Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors.
8842729 1996 Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23.
7719335 1995 An imprinted gene(s) for diabetes?