This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Åström, A.-K. Articles by Stenman, G. Search for Related Content PubMed PubMed Citation Articles by Åström, A.-K. Articles by Stenman, G.

Conserved Mechanism of PLAG1 Activation in Salivary Gland Tumors with and without Chromosome 8q12 Abnormalities

Identification of SII as a New Fusion Partner Gene¹

Laboratory of Cancer Genetics, Department of Pathology, Göteborg University, SE-413 45 Göteborg, Sweden [A-K. Å., E. R., B. W., J. M., G. S.]; Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium [M. L. V., K. K., W. V. d. V.]; Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden [N. M.]; and Department of Pathology, Central Hospital, SE-541 85 Skövde, Sweden [J. M.]

We have previously shown (K. Kas et al., Nat. Genet., 15: 170–174, 1997) that the developmentally regulated zinc finger gene pleomorphic adenoma gene 1 (PLAG1) is the target gene in 8q12 in pleomorphic adenomas of the salivary glands with t(3;8)(p21;q12) translocations. The t(3;8) results in promoter swapping between PLAG1 and the constitutively expressed gene for ß-catenin (CTNNB1), leading to activation of PLAG1 expression and reduced expression of CTNNB1. Here we have studied the expression of PLAG1 by Northern blot analysis in 47 primary benign and malignant human tumors with or without cytogenetic abnormalities of 8q12. Overexpression of PLAG1 was found in 23 tumors (49%). Thirteen of 17 pleomorphic adenomas with a normal karyotype and 5 of 10 with 12q13–15 abnormalities overexpressed PLAG1, which demonstrates that PLAG1 activation is a frequent event in adenomas irrespective of karyotype. In contrast, PLAG1 was overexpressed in only 2 of 11 malignant salivary gland tumors analyzed, which suggests that, at least in salivary gland tumors, PLAG1 activation preferentially occurs in benign tumors. PLAG1 overexpression was also found in three of nine mesenchymal tumors, i.e., in two uterine leiomyomas and one leiomyosarcoma. RNase protection, rapid amplification of 5'-cDNA ends (5'-RACE), and reverse transcription-PCR analyses of five adenomas with a normal karyotype revealed fusion transcripts in three tumors. Nucleotide sequence analysis of these showed that they contained fusions between PLAG1 and CTNNB1 (one case) or PLAG1 and a novel fusion partner gene, i.e., the gene encoding the transcription elongation factor SII (two cases). The fusions occurred in the 5' noncoding region of PLAG1, leading to exchange of regulatory control elements and, as a consequence, activation of PLAG1 gene expression. Because all of the cases had grossly normal karyotypes, the rearrangements must result from cryptic rearrangements. The results suggest that in addition to chromosomal translocations and cryptic rearrangements, PLAG1 may also be activated by mutations or indirect mechanisms. Our findings establish a conserved mechanism of PLAG1 activation in salivary gland tumors with and without 8q12 aberrations, which indicates that such activation is a frequent event in these tumors.

This article has been cited by other articles:

				L. Queimado, D. Obeso, M. D. Hatfield, Y. Yang, D. M. Thompson, and A. M.C. Reis Dysregulation of Wnt Pathway Components in Human Salivary Gland Tumors Arch Otolaryngol Head Neck Surg, January 1, 2008; 134(1): 94 - 101. [Abstract] [Full Text] [PDF]

				G. Zheng and Y.-C. Yang Sumoylation and Acetylation Play Opposite Roles in the Transactivation of PLAG1 and PLAGL2 J. Biol. Chem., December 9, 2005; 280(49): 40773 - 40781. [Abstract] [Full Text] [PDF]

				J. Declercq, F. Van Dyck, C. V. Braem, I. C. Van Valckenborgh, M. Voz, M. Wassef, L. Schoonjans, B. Van Damme, L. Fiette, and W. J.M. Van de Ven Salivary Gland Tumors in Transgenic Mice with Targeted PLAG1 Proto-Oncogene Overexpression Cancer Res., June 1, 2005; 65(11): 4544 - 4553. [Abstract] [Full Text] [PDF]

				F. Van Dyck, E. L. D. Delvaux, W. J. M. Van de Ven, and M. V. Chavez Repression of the Transactivating Capacity of the Oncoprotein PLAG1 by SUMOylation J. Biol. Chem., August 20, 2004; 279(34): 36121 - 36131. [Abstract] [Full Text] [PDF]

				C. V. Braem, K. Kas, E. Meyen, M. Debiec-Rychter, W. J. M. Van de Ven, and M. L. Voz Identification of a Karyopherin alpha 2 Recognition Site in PLAG1, Which Functions As a Nuclear Localization Signal J. Biol. Chem., May 24, 2002; 277(22): 19673 - 19678. [Abstract] [Full Text] [PDF]

				F. Francioso, F. Carinci, L. Tosi, L. Scapoli, F. Pezzetti, E. Passerella, R. Evangelisti, A. Pastore, S. Pelucchi, A. Piattelli, et al. Identification of Differentially Expressed Genes in Human Salivary Gland Tumors by DNA Microarrays Mol. Cancer Ther., May 1, 2002; 1(7): 533 - 538. [Abstract] [Full Text] [PDF]

				K. Hensen, I. C. C. Van Valckenborgh, K. Kas, W. J. M. Van de Ven, and M. L. Voz The Tumorigenic Diversity of the Three PLAG Family Members Is Associated with Different DNA Binding Capacities Cancer Res., March 1, 2002; 62(5): 1510 - 1517. [Abstract] [Full Text] [PDF]

				E. Roijer, A. Nordkvist, A.-K. Strom, W. Ryd, M. Behrendt, J. Bullerdiek, J. Mark, and G. Stenman Translocation, Deletion/Amplification, and Expression of HMGIC and MDM2 in a Carcinoma ex Pleomorphic Adenoma Am. J. Pathol., February 1, 2002; 160(2): 433 - 440. [Abstract] [Full Text] [PDF]

				M. K. Hibbard, H. P. Kozakewich, P. D. Cin, R. Sciot, X. Tan, S. Xiao, and J. A. Fletcher PLAG1 Fusion Oncogenes in Lipoblastoma Cancer Res., September 1, 2000; 60(17): 4869 - 4872. [Abstract] [Full Text]

				M. L. Voz, N. S. Agten, W. J. M. Van de Ven, and K. Kas PLAG1, the Main Translocation Target in Pleomorphic Adenoma of the Salivary Glands, Is a Positive Regulator of IGF-II Cancer Res., January 1, 2000; 60(1): 106 - 113. [Abstract] [Full Text]

				H. Sjogren, J. Meis-Kindblom, L.-G. Kindblom, P. Aman, and G. Stenman Fusion of the EWS-related Gene TAF2N to TEC in Extraskeletal Myxoid Chondrosarcoma Cancer Res., October 1, 1999; 59(20): 5064 - 5067. [Abstract] [Full Text] [PDF]