Reviewed, UniProtKB/Swiss-Prot Q6DJT9 (PLAG1_HUMAN)

Names and origin

Protein names

Recommended name:
    Zinc finger protein PLAG1
Alternative name(s):
    Pleiomorphic adenoma gene 1 protein

Gene names

Name:

PLAG1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	500 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcription factor whose activation results in up-regulation of target genes, such as IGFII, leading to uncontrolled cell proliferation: when overexpressed in cultured cells, higher proliferation rate and transformation are observed. Other target genes such as CRLF1, CRABP2, CRIP2, PIGF are strongly induced in cells with PLAG1 induction. Proto-oncogene whose ectopic expression can trigger the development of pleomorphic adenomas of the salivary gland and lipoblastomas. Overexpression is associated with up-regulation of IGFII, is frequently observed in hepatoblastoma, common primary liver tumor in childhood. Cooperates with CBFB-MYH11, a fusion gene important for myeloid leukemia. Ref.9 Ref.11 Ref.13
Subunit structure	Interacts with KPNA2, which escorts protein to the nucleus via interaction with nuclear localization signal. Interacts with E3 SUMO-protein ligase PIAS1, PIAS2 and PIAS4. Ref.10 Ref.12
Subcellular location	Nucleus. Note: Strong nucleolar localization when sumoylation is inhibited. Ref.10 Ref.7 Ref.15
Tissue specificity	Expressed in fetal tissues such as lung, liver and kidney. Not detected or weak detection in normal adult tissues, but highly expressed in salivary gland with benign or malignant pleiomorphic adenomas with or without 8q12 abberations, with preferential occurrence in benign tumors. Ref.11 Ref.1 Ref.4 Ref.6
Domain	C2H2-type zinc fingers 3 interacts with DNA-binding site G-clusterinc fingers. C2H2-type zinc fingers 6 and 7 interact with DNA-binding site core sequence.
Post-translational modification	Sumoylated by SUMO1; which inhibits transcriptional activity, but does not affect nuclear localization. Blockers of sumoylation pathway such as SENP3 and inactive UBE2I increases transcriptional capacity. Sumoylation is increased in the presence of PIAS1. Ref.12 Ref.15 Acetylated by lysine acetyltransferase EP300; which activates transcriptional capacity. Lysine residues that are sumoylated also seem to be target for acetylation. Ref.12 Ref.15
Involvement in disease	A chromosomal rearrangement involving PLAG1 may be a cause of salivary gland pleiomorphic adenomas (PA) [181030]. Pleiomorphic adenomas are the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with constituvely expressed beta-catenin/CTNNB1. Fusion occurs in the 5'-regulatory regions, leading to promoter swapping between the 2 genes and activation of PLAG1 expression in adenomas. The chimeric transcript is formed by fusion of CTNNB1 exon 1 to PLAG1 exon 3. Reciprocal fusion transcript consisting of PLAG1 exon 1 and CTNNB1 exon 2-16 is also revealed in some adenomas. Translocation t(3;8)(p21;q12) with transcription elongation factor SII/TCEA1. The fusion transcript is composed of 5'-non-coding sequences as well as 63 nucleotides of the coding region of TCEA1 fused to the acceptor splice site of PLAG1 exon 3. The fusion transcript encodes a truncated TCEA1-PLAG1 protein of 90 AA as well as an apparently normal PLAG1 protein. Reciprocal fusion transcript PLAG1-TCEA1 is also present in one adenoma. Translocation t(5;8)(p13;q12) with leukemia inhibitory factor receptor LIFR. This fusion occured in the 5'-non-coding sequences of both genes, exchanging regulatory control element while preserving the coding sequences. Translocation t(6;8)(p21.3-22;q13) with Coiled-coil-helix-coiled-coil-helix domain-containing protein 7/CHCHD7. Fusion occurs in the 5' regulatory regions, leading to promoter swapping and up-regulation of PLAG1 expression. Ectopic expression of PLAG1 under the control of promoters of distinct translocation partner genes is a general pathogenetic mechanism for pleiomorphic adenomas with 8q aberrations. These fusion genes are likely to be found in adenomas with normal karyotype as this subgroup of tumors also exhibit PLAG1 activation. A chromosomal rearrangement involving PLAG1 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. 8q12.1 to 8q24.1 intrachromosomal rearrangement with hyaluronic acid synthase 2/HAS2 results in promoter swapping and activation of PLAG1 expression. The breakpoint of HAS2 gene is in PLAG1 intron 1, whereas its coding sequence starts at exon 2 or exon 3. Translocation t(7;8)(p22;q13) with collagen 1A2/COL1A2. Fusion transcript COL1A2-PLAG1 as well as HAS2-PLAG1 encode a full-length PLAG1 protein.
Miscellaneous	Residual nuclear import after mutation of the nuclear localization signal is assigned to zinc finger domains of PLAG1. When cultured cells transformed by PLAG1 overexpression are injected in nude mouse, rapidly growing tumors (fibrosarcomaS) are observed at the site of inoculation.
Sequence similarities	Belongs to the krueppel C2H2-type zinc-finger protein family. Contains 7 C2H2-type zinc fingers.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Disease	Proto-oncogene
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Activator
PTM	Acetylation Isopeptide bond Ubl conjugation
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	regulation of transcription Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	transcription factor activity Ref.4 Traceable author statement. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 500	500	Zinc finger protein PLAG1		PRO_0000295107
Regions
	Zinc finger	34 – 56	23	C2H2-type 1
	Zinc finger	62 – 86	25	C2H2-type 2
	Zinc finger	92 – 114	23	C2H2-type 3
	Zinc finger	121 – 143	23	C2H2-type 4
	Zinc finger	150 – 172	23	C2H2-type 5
	Zinc finger	185 – 207	23	C2H2-type 6
	Zinc finger	213 – 236	24	C2H2-type 7
	Region	2 – 84	83	Interacts with KPNA2
	Region	41 – 242	202	Decreased nuclear import with localization in the nucleus but also in the cytoplasm
	Region	243 – 500	258	Activates transcription; Inhibition of nuclear import due to lack of NLS and KPNA2 interaction
	Region	243 – 384	142	Repression domain; contains 3 sumoylation motifs and massively decrease transcription activity
	Region	385 – 500	116	Massively activates transcription
	Motif	22 – 25	4	Nuclear localization signal
Amino acid modifications
	Cross-link	244		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
	Cross-link	263		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
Natural variations
	Natural variant	458	1	P → T: dbSNP rs35883156. Ref.1		VAR_033212
Experimental info
	Mutagenesis	23 – 24	2	RK → AA: Inhibition of KPNA2 interaction when mutation occurs in the NLS; decreased nuclear import with localization in the nucleus but also in the cytoplasm; Complete inhibition of nuclear import When associated with a lack of zinc-finger domains. Ref.10
	Mutagenesis	31 – 32	2	RK → AA: No inhibition of KPNA2 interaction and no change in nuclear import. Ref.10
	Mutagenesis	92	1	H → A: Prevents formation of functional zinc-finger 3; induces drastic decrease of DNA affinity and complete modification of DNA binding specificity. Ref.10 Ref.7
	Mutagenesis	227	1	H → A: Prevents formation of functional zinc-finger 7 and inhibits DNA binding; No proliferation and transformation of cultured cells. Ref.9 Ref.10 Ref.7
	Mutagenesis	244	1	K → R: Abolishes single and double sumoylation; nuclear localization conserved. Increases transcriptional activity and inhibits repression domain activity; when associated with R-263 and R-353. Ref.10 Ref.12 Ref.15
	Mutagenesis	263	1	K → R: Decreases sumoylation; Abolishes double sumoylation only; Nuclear localization conserved. Increases transcriptional activity and inhibits repression domain activity; when associated with R-244 and R-353. Ref.10 Ref.12 Ref.15
	Mutagenesis	339	1	T → A: No effect on transcription activation capacity. Ref.10 Ref.4
	Mutagenesis	340	1	S → A: No effect on transcription activation capacity. Ref.10 Ref.4
	Mutagenesis	353	1	K → R: No effect on sumoylation. Increases transcriptional activity and inhibits repression domain activity; when associated with R-244 and R-263. Ref.10 Ref.12 Ref.15
	Sequence conflict	276	1	E → D in BAD92368. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q6DJT9-1 [UniParc]. Last modified August 16, 2004. Version 1. Checksum: CF022A132A1BFD43	FASTA	500	55,909
	10 20 30 40 50 60 MATVIPGDLS EVRDTQKVPS GKRKRGETKP RKNFPCQLCD KAFNSVEKLK VHSYSHTGER 70 80 90 100 110 120 PYKCIQQDCT KAFVSKYKLQ RHMATHSPEK THKCNYCEKM FHRKDHLKNH LHTHDPNKET 130 140 150 160 170 180 FKCEECGKNY NTKLGFKRHL ALHAATSGDL TCKVCLQTFE STGVLLEHLK SHAGKSSGGV 190 200 210 220 230 240 KEKKHQCEHC DRRFYTRKDV RRHMVVHTGR KDFLCQYCAQ RFGRKDHLTR HMKKSHNQEL 250 260 270 280 290 300 LKVKTEPVDF LDPFTCNVSV PIKDELLPVM SLPSSELLSK PFTNTLQLNL YNTPFQSMQS 310 320 330 340 350 360 SGSAHQMITT LPLGMTCPID MDTVHPSHHL SFKYPFSSTS YAISIPEKEQ PLKGEIESYL 370 380 390 400 410 420 MELQGGVPSS SQDSQASSSS KLGLDPQIGS LDDGAGDLSL SKSSISISDP LNTPALDFSQ 430 440 450 460 470 480 LFNFIPLNGP PYNPLSVGSL GMSYSQEEAH SSVSQLPPQT QDLQDPANTI GLGSLHSLSA 490 500 AFTSSLSTST TLPRFHQAFQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations." Kas K., Voz M.L., Roeijer E., Astroem A.-K., Meyen E., Stenman G., Van de Ven W.J.M. Nat. Genet. 15:170-174(1997) [PubMed: 9020842] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, CHROMOSOMAL TRANSLOCATION WITH CTNNB1, VARIANT THR-458.
[2]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[4]	"Transcriptional activation capacity of the novel PLAG family of zinc finger proteins." Kas K., Voz M.L., Hensen K., Meyen E., Van de Ven W.J.M. J. Biol. Chem. 273:23026-23032(1998) [PubMed: 9722527] [Abstract] Cited for: TISSUE SPECIFICITY, MUTAGENESIS OF THR-339 AND SER-340.
[5]	"The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter." Voz M.L., Astrom A.-K., Kas K., Mark J., Stenman G., Van de Ven W.J.M. Oncogene 16:1409-1416(1998) [PubMed: 9525740] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH LIFR.
[6]	"Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene." Astroem A.-K., Voz M.L., Kas K., Roeijer E., Wedell B., Mandahl N., Van de Ven W., Mark J., Stenman G. Cancer Res. 59:918-923(1999) [PubMed: 10029085] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH CTNNB1 AND TCEA1, TISSUE SPECIFICITY.
[7]	"PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II." Voz M.L., Agten N.S., Van de Ven W.J.M., Kas K. Cancer Res. 60:106-113(2000) [PubMed: 10646861] [Abstract] Cited for: SUBCELLULAR LOCATION, DNA-BINDING, MUTAGENESIS OF HIS-92 AND HIS-227.
[8]	"PLAG1 fusion oncogenes in lipoblastoma." Hibbard M.K., Kozakewich H.P., Dal Cin P., Sciot R., Tan X., Xiao S., Fletcher J.A. Cancer Res. 60:4869-4872(2000) [PubMed: 10987300] [Abstract] Cited for: CHROMOSOMAL REARRANGEMENT WITH HAS2 AND COL1A2.
[9]	"The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities." Hensen K., Van Valckenborgh I.C.C., Kas K., Van de Ven W.J.M., Voz M.L. Cancer Res. 62:1510-1517(2002) [PubMed: 11888928] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF HIS-227.
[10]	"Identification of a karyopherin alpha 2 recognition site in PLAG1, which functions as a nuclear localization signal." Braem C.V., Kas K., Meyen E., Debiec-Rychter M., Van De Ven W.J.M., Voz M.L. J. Biol. Chem. 277:19673-19678(2002) [PubMed: 11882654] [Abstract] Cited for: INTERACTION WITH KPNA2, SUBCELLULAR LOCATION, MUTAGENESIS OF 23-ARG-LYS-24 AND 31-ARG-LYS-32.
[11]	"Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma." Zatkova A., Rouillard J.-M., Hartmann W., Lamb B.J., Kuick R., Eckart M., von Schweinitz D., Koch A., Fonatsch C., Pietsch T., Hanash S.M., Wimmer K. Genes Chromosomes Cancer 39:126-137(2004) [PubMed: 14695992] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[12]	"Repression of the transactivating capacity of the oncoprotein PLAG1 by SUMOylation." Van Dyck F., Delvaux E.L.D., Van de Ven W.J.M., Chavez M.V. J. Biol. Chem. 279:36121-36131(2004) [PubMed: 15208321] [Abstract] Cited for: SUMOYLATION, MUTAGENESIS OF LYS-244; LYS-263 AND LYS-353, INTERACTION WITH PIAS PROTEINS.
[13]	"Microarray screening for target genes of the proto-oncogene PLAG1." Voz M.L., Mathys J., Hensen K., Pendeville H., Van Valckenborgh I., Van Huffel C., Chavez M., Van Damme B., De Moor B., Moreau Y., Van de Ven W.J. Oncogene 23:179-191(2004) [PubMed: 14712223] [Abstract] Cited for: FUNCTION.
[14]	"PLAG1-HAS2 fusion in lipoblastoma with masked 8q intrachromosomal rearrangement." Morerio C., Rapella A., Rosanda C., Tassano E., Gambini C., Romagnoli G., Panarello C. Cancer Genet. Cytogenet. 156:183-184(2005) [PubMed: 15642402] [Abstract] Cited for: CHROMOSOMAL REARRANGEMENT WITH HAS2.
[15]	"Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2." Zheng G., Yang Y.-C. J. Biol. Chem. 280:40773-40781(2005) [PubMed: 16207715] [Abstract] Cited for: SUMOYLATION, ACETYLATION, MUTAGENESIS OF LYS-244; LYS-263 AND LYS-353, SUBCELLULAR LOCATION.
[16]	"CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas." Asp J., Persson F., Kost-Alimova M., Stenman G. Genes Chromosomes Cancer 45:820-828(2006) [PubMed: 16736500] [Abstract] Cited for: CHROMOSOMAL REARRANGEMENT WITH CHCHD7 AND TCEA1.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases
EMBLGenBankDDBJ	U65002 mRNA. Translation: AAC50995.1. AB209131 mRNA. Translation: BAD92368.1. Different initiation. BC075047 mRNA. Translation: AAH75047.1. BC075048 mRNA. Translation: AAH75048.1.
IPI	IPI00787796.
RefSeq	NP_001108106.1. NP_002646.2.
UniGene	Hs.14968
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	Q6DJT9.
PTM databases
PhosphoSite	Q6DJT9.
Genome annotation databases
Ensembl	ENST00000316981; ENSP00000325546; ENSG00000181690; Homo sapiens. [Genome view] ENST00000423799; ENSP00000404067; ENSG00000181690; Homo sapiens. [Genome view] ENST00000429357; ENSP00000416537; ENSG00000181690; Homo sapiens. [Genome view]
GeneID	5324.
KEGG	hsa:5324.
UCSC	uc003xsq.2. human.
Organism-specific databases
CTD	5324.
GeneCards	GC08M057236.
HGNC	HGNC:9045. PLAG1.
HPA	HPA005462.
MIM	181030. phenotype. 603026. gene.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q6DJT9.
OMA	DMDAVHP.
Gene expression databases
ArrayExpress	Q6DJT9.
Bgee	Q6DJT9.
CleanEx	HS_PLAG1.
Genevestigator	Q6DJT9.
Family and domain databases
InterPro	IPR007087. Znf_C2H2. IPR015880. Znf_C2H2-like. IPR013087. Znf_C2H2/integrase_DNA-bd. [Graphical view]
Gene3D	G3DSA:3.30.160.60. Znf_C2H2/integrase_DNA-bd. 1 hit.
Pfam	PF00096. zf-C2H2. 7 hits. [Graphical view]
ProDom	PD000003. Znf_C2H2. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00355. ZnF_C2H2. 7 hits. [Graphical view]
PROSITE	PS00028. ZINC_FINGER_C2H2_1. 7 hits. PS50157. ZINC_FINGER_C2H2_2. 7 hits. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	20594.
SOURCE	Search...

Entry information

Entry name

PLAG1_HUMAN

Accession

Primary (citable) accession number: Q6DJT9
Secondary accession number(s): Q59GH8, Q9Y4L2

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 10, 2007
Last sequence update:	August 16, 2004
Last modified:	November 3, 2009
This is version 57 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.