PLAGL1 (Pleomorphic adenoma gene-like 1)

2007-08-01   Abbas 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

Identity

HGNC
LOCATION
6q24.2
LOCUSID
ALIAS
LOT1,ZAC,ZAC1
FUSION GENES

DNA/RNA

Atlas Image
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)

Proteins

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 name
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 name
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

Bibliography

Pubmed IDLast YearTitleAuthors
170634612007LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions.Abdollahi A et al
124736472003LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer.Abdollahi A et al
109360462000A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC.Arima T et al
158887262005ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.Arima T et al
165751872006Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region during oogenesis.Arima T et al
169284282006The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice.Arima T et al
171788962006Peroxisome proliferator-activated receptor gamma is a Zac target gene mediating Zac antiproliferation.Barz T et al
161794952005The candidate tumor suppressor gene ZAC is involved in keratinocyte differentiation and its expression is lost in basal cell carcinomas.Basyuk E et al
113138692001Alternative splicing of the imprinted candidate tumor suppressor gene ZAC regulates its antiproliferative and DNA binding activities.Bilanges B et al
127113702003Developmental expression of the cell cycle and apoptosis controlling gene, Lot1, in the rat cerebellum and in cultures of cerebellar granule cells.Ciani E et al
160614852005Cyclic AMP-mediated regulation of transcription factor Lot1 expression in cerebellar granule cells.Contestabile A et al
155819452004Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer.Cvetkovic D et al
97952211998Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice.Gillardon F et al
118889282002The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities.Hensen K et al
168097862006Multitasking C2H2 zinc fingers link Zac DNA binding to coordinated regulation of p300-histone acetyltransferase activity.Hoffmann A et al
113601972001Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1.Huang SM et al
106697602000Mouse Zac1, a transcriptional coactivator and repressor for nuclear receptors.Huang SM et al
157510352005Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.Kamikihara T et al
106555562000The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes.Kamiya M et al
97225271998Transcriptional activation capacity of the novel PLAG family of zinc finger proteins.Kas K et al
150547372004Loss of expression of ZAC/LOT1 in squamous cell carcinomas of head and neck.Koy S et al
119353192002Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.Mackay DJ et al
111563672000The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas.Pagotto U et al
107578142000Zac1 (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 et al
161124212005The PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors.Poulin H et al
121191042002The mouse Zac1 locus: basis for imprinting and comparison with human ZAC.Smith RJ et al
91842261997Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.Spengler D et al
115788772001Expression 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 et al
153506442004Zac1 is up-regulated in neural cells of the limbic system of mouse brain following seizures that provoke strong cell activation.Valente T et al
158440992005Zac1 is expressed in progenitor/stem cells of the neuroectoderm and mesoderm during embryogenesis: differential phenotype of the Zac1-expressing cells during development.Valente T et al
173414872007Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters.Valleley EM et al
170843622006Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth.Varrault A et al
176973792007DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth.Wu C et al
173764042007Physical and functional interactions of human papillomavirus E2 protein with nuclear receptor coactivators.Wu MH et al

Other Information

Locus ID:

NCBI: 5325
MIM: 603044
HGNC: 9046
Ensembl: ENSG00000118495

Variants:

dbSNP: 5325
ClinVar: 5325
TCGA: ENSG00000118495
COSMIC: PLAGL1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000118495ENST00000354765Q9UM63
ENSG00000118495ENST00000360537Q9UM63
ENSG00000118495ENST00000367571Q9UM63
ENSG00000118495ENST00000367572Q9UM63
ENSG00000118495ENST00000392307Q68DN7
ENSG00000118495ENST00000416623Q9UM63
ENSG00000118495ENST00000417959Q9UM63
ENSG00000118495ENST00000437412Q9UM63
ENSG00000118495ENST00000444202Q9UM63
ENSG00000118495ENST00000625622Q9UM63
ENSG00000118495ENST00000626294A0A0D9SGF7
ENSG00000118495ENST00000626373A1YLA2
ENSG00000118495ENST00000626462A0A0D9SFM8
ENSG00000118495ENST00000627449A0A0D9SEQ4
ENSG00000118495ENST00000628651A0A0D9SFI7
ENSG00000118495ENST00000629195A1YLA1
ENSG00000118495ENST00000647880Q9UM63
ENSG00000118495ENST00000647988A0A3B3IRN7
ENSG00000118495ENST00000649211Q9UM63
ENSG00000118495ENST00000649307Q9UM63
ENSG00000118495ENST00000650125Q9UM63

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
TP53 Regulates Transcription of Cell Cycle GenesREACTOMER-HSA-6791312
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertainREACTOMER-HSA-6804115

References

Pubmed IDYearTitleCitations
106555562000The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes.55
152868002004Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.42
158887262005ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.35
125294032003Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding.27
173414872007Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters.26
204875062010A whole genome association study of mother-to-child transmission of HIV in Malawi.26
124736472003LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer.25
243167532014Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort.24
155926632004Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.23
119353192002Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.22

Citation

Abbas Abdollahi

PLAGL1 (Pleomorphic adenoma gene-like 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-08-01

Online version: http://atlasgeneticsoncology.org/gene/41737/plagl1