Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

PLAG1 (Pleomorphic adenoma 1) David Gisselsson Department of Clinical Genetics, Lund University Hospital, 221 85 Lund, Sweden (DG)

Published in Atlas Database: June 2002 Online updated version: http://AtlasGeneticsOncology.org/Genes/PLAG1ID74.html DOI: 10.4267/2042/37897 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Localisation Nuclear. HGNC (Hugo): PLAG1 Function Location: 8q12 One of the N-terminal nuclear localisation signals Local order: (316 cR / 86 Mb from 8pter) (NLS1) interacts with a2, which escorts into the nucleus. Three of the seven Zn-finger DNA/RNA domains are responsible for interaction with DNA and Description PLAG1 specifically activates transcription from its consensus binding site. Potential PLAG1 binding sites 7313 bp, 5 exons, 4 introns. have been found in the promoter of IGF2. Transcription Homology At least two splicing variants, including and excluding Mouse and rat Plag1. the second exon. Mutations Somatic Description Involved in rearrangements in epithelial 500 amino acids with at least three functional regions: and mesenchymal tumours. These are typically 1. Two N-terminal nuclear localisation signals, 2. complex structural abnormalities, resulting in an Seven canonical zinc-finger domains, 3. A serine rich exchange of regulatory elements and abnormal C-terminus. expression of PLAG1. Expression Heart, placenta, spleen, prostate, testis, ovary, small intestine, several tumours.

Schematic view of the gene with approximate sizes of introns (kb) and exons (bp); the coding region (violet) translates into a 500 amino acid product with three functional subunits.

Atlas Genet Cytogenet Oncol Haematol. 2002; 6(4) 283

PLAG1 (Pleomorphic adenoma gene 1) Gisselsson D

Implicated in References Pleomorphic adenoma of the salivary Kas K, Röijer E, Voz M, Meyen E, Stenman G, Van de Ven WJ. A 2-Mb YAC contig and physical map covering the gland chromosome 8q12 breakpoint cluster region in pleomorphic adenomas of the salivary glands. Genomics. 1997 Aug Disease 1;43(3):349-58 Benign epithelial tumour. Kas K, Voz ML, Röijer E, Aström AK, Meyen E, Stenman G, Prognosis Van de Ven WJ. Promoter swapping between the for a Recovery after surgical removal. novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat Genet. 1997 Cytogenetics Feb;15(2):170-4 The most common breakpoints are 3p21, 8q12, and Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ. 12q15. Transcriptional activation capacity of the novel PLAG family of Hybrid/Mutated gene zinc finger proteins. J Biol Chem. 1998 Sep 4;273(36):23026- 32 The following translocations have been reported to result in hybrid genes involving PLAG1: Voz ML, Aström AK, Kas K, Mark J, Stenman G, Van de Ven - t(3;8)(p21;q12): CTNNB1 CTNNB1/PLAG1 WJ. The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression - t(5;8)(p13;q12): LIFR/PLAG1 under control of the LIFR promoter. Oncogene. 1998 Also, rearrangements between PLAG1 and TCEA1 Mar;16(11):1409-16 have been detected in cases with normal karyotypes. Aström AK, Voz ML, Kas K, Röijer E, Wedell B, Mandahl N, Abnormal protein Van de Ven W, Mark J, Stenman G. Conserved mechanism of Fusions occur in the 5' regulatory regions, leading to PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new promoter swapping and activation of PLAG1 fusion partner gene. Cancer Res. 1999 Feb 15;59(4):918-23 expression while preserving coding sequences. Queimado L, Lopes C, Du F, Martins C, Bowcock AM, Soares Carcinoma ex pleomorphic adenoma J, Lovett M. Pleomorphic adenoma gene 1 is expressed in cultured benign and malignant salivary gland tumor cells. Lab Disease Invest. 1999 May;79(5):583-9 Malignant epithelial tumour arising from pleomorphic Röijer E, Kas K, Behrendt M, Van de Ven W, Stenman G. adenoma. Fluorescence in situ hybridization mapping of breakpoints in Prognosis pleomorphic adenomas with 8q12-13 abnormalities identifies a subgroup of tumors without PLAG1 involvement. Genes 30% five-year survival. Cancer. 1999 Jan;24(1):78-82 Cytogenetics Astrom A, D'Amore ES, Sainati L, Panarello C, Morerio C, Complex karyotype including t(3;8)(p23;q12). Mark J, Stenman G. Evidence of involvement of the PLAG1 Hybrid/Mutated gene gene in lipoblastomas. Int J Oncol. 2000 Jun;16(6):1107-10 Intragenic PLAG1 rearrangements demonstrated by Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao fluorescence in situ hybridisation. S, Fletcher JA. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res. 2000 Sep 1;60(17):4869-72 Lipoblastoma Voz ML, Agten NS, Van de Ven WJ, Kas K. PLAG1, the main Disease translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res. 2000 Jan Benign fat-forming tumour of childhood. 1;60(1):106-13 Prognosis Voz ML, Van de Ven WJ, Kas K. First insights into the Recovery after surgical removal. molecular basis of pleomorphic adenomas of the salivary Cytogenetics glands. Adv Dent Res. 2000 Dec;14:81-3 Structural abnormalities involving 8q11-13. Debiec-Rychter M, Van Valckenborgh I, Van den Broeck C, Hagemeijer A, Van de Ven WJ, Kas K, Van Damme B, Voz Hybrid/Mutated gene ML. Histologic localization of PLAG1 (pleomorphic adenoma The following rearrangements have been reported to gene 1) in pleomorphic adenoma of the salivary gland: result in hybrid genes involving PLAG1: cytogenetic evidence of common origin of phenotypically - del(8)(q12q24), r(8): HAS2/PLAG1 diverse cells. Lab Invest. 2001 Sep;81(9):1289-97 - t(7;8)(p22;q13): COL1A2/HAS2 Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, Kozakewich HP, Fletcher JA. PLAG1 alterations in Abnormal protein lipoblastoma: involvement in varied mesenchymal cell types Fusions occur in the 5' regulatory regions, leading and evidence for alternative oncogenic mechanisms. Am J promoter swapping and activation of PLAG1 Pathol. 2001 Sep;159(3):955-62 expression while preserving coding sequences.

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Jin C, Martins C, Jin Y, Wiegant J, Wennerberg J, Dictor M, Enlund F, Nordkvist A, Sahlin P, Mark J, Stenman G. Gisselsson D, Strömbeck B, Fonseca I, Mitelman F, Tanke HJ, Expression of PLAG1 and HMGIC proteins and fusion Höglund M, Mertens F. Characterization of chromosome transcripts in radiation-associated pleomorphic adenomas. Int aberrations in salivary gland tumors by FISH, including J Oncol. 2002 Apr;20(4):713-6 multicolor COBRA-FISH. Genes Chromosomes Cancer. 2001 Feb;30(2):161-7 Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML. The tumorigenic diversity of the three PLAG family Szpirer C, Kas K, Laes JF, Rivière M, Van Vooren P, Szpirer J. members is associated with different DNA binding capacities. Assignment of the rat pleiomorphic adenoma genes (Plag1, Cancer Res. 2002 Mar 1;62(5):1510-7 Plagl1, Plagl2) by in situ hybridization and radiation hybrid mapping. Cytogenet Cell Genet. 2001;94(1-2):94-5 This article should be referenced as such: Braem CV, Kas K, Meyen E, Debiec-Rychter M, Van De Ven Gisselsson D. PLAG1 (Pleomorphic adenoma gene 1). Atlas WJ, Voz ML. Identification of a karyopherin alpha 2 recognition Genet Cytogenet Oncol Haematol. 2002; 6(4):283-285. site in PLAG1, which functions as a nuclear localization signal. J Biol Chem. 2002 May 31;277(22):19673-8

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