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PLAG1

MIM.603026 8q12

Tuesday 2 March 2004

Definition: Pleomorphic Adenoma Gene 1 (PLAG1) is a proto-oncogene on human chromosome 8q12 whose oncogenic activation is a crucial event in the development of several human tumours, so far including pleomorphic adenoma of the salivary glands, lipoblastoma, hepatoblastoma, and AML.

Functions

As PLAG1 is a transcription factor, able to activate transcription through the binding to the consensus sequence GRGGC(N)(6-8)GGG, its ectopic expression presumably results in the deregulation of target genes, leading to uncontrolled cell proliferation.

PLAG1 encodes a developmentally regulated, SUMOylated and phosphorylated zinc finger transcription factor, recognizes a specific bipartite DNA consensus sequence regulating expression of a spectrum of target genes, and has two structurally related family members, i.e. the PLAGL1 and PLAGL2 gene.

Pathology

The oncogenic potential of PLAG1 has been confirmed in in vitro experiments.

IGF-II and IGF-IR have been identified as key pathway elements in these tumors, similarly as in many human tumours. PLAG1 has been shown be a transcriptional activator of IGF2 in several tumor types.

The PLAG1 proto-oncogene was discovered by studying the t(3;8)(p21;q12) chromosome translocation, which frequently occurs in human pleomorphic adenomas of the salivary glands.

Ectopic PLAG1 overexpression, in many cases due to promoter swapping, causes deregulation of expression of a variety of PLAG1 target genes. This was established by microarray analysis, which indicated that the oncogenic capability of PLAG1 is mediated, at least partly, by the IGF-II mitogenic signaling pathway.

Oncogenic activation of PLAG1 is also a crucial event in other human tumours, including lipoblastoma, hepatoblastoma, and AML.

The oncogenic potential of PLAG1 has been confirmed in in vitro experiments, which also established IGF-II and IGF-IR as key pathway elements, similarly as in many human tumours.

PLAGLs

In contrast to the pleiotropic oncogenic potential of PLAG1, its family member PLAGL1, which is localized in an imprinted region on chromosome 6q24-25, is defined by various studies as a tumour-suppressor gene.

Finally, the PLAGL2 family member is not only structurally but also functionally more closely related to PLAG1 and has recently also been implicated in AML, both in humans and in genetically modified mice.

Pathology

- PLAG1 amplification and overexpression in tumors

  • pleomorphic adenoma of the salivary glands
  • malignant mixed tumor of salivary gland (#15262430#)
  • lipoblastoma
  • hepatoblastoma (#14695992#)

- PLAG1 rearrangement by translocation

  • in lipoblastoma (#10987300#, #10811981#)
    • 8q12 rearrangements
      • PLAG1-HAS2 fusion (#15642402#)
  • in pleiomorphic adenoma (#10646861#)
    • promoter swapping between the genes for zinc finger protein PLAG1 and beta-catenin CTNNB1 in pleiomorphic adenoma with t(3;8)(p21;q12) translocations (#9020842#)
    • CHCHD7/PLAG1 gene fusion in pleiomorphic adenoma (#16736500#)
    • TCEA1/PLAG1 gene fusion in pleiomorphic adenoma (#16736500#)

- IGF2 regulator role of PLAG1 in hepatoblastoma (#14695992#)

  • PLAG1 has been shown be a transcriptional activator of IGF2 in other tumor types (#14695992#)

Immunochemistry: #11555676#, #15920557#, #20055685#

Animal models

Generation of conditional PLAG1 transgenic mouse strains revealed tumour development in a variety of targeted tissues, establishing the versatility of the PLAG1 oncogene.

Generation of conditional PLAG1 transgenic mouse strains revealed tumour development in a variety of targeted tissues, establishing the versatility of the PLAG1 oncogene and pointing towards a window of opportunity for therapeutic intervention studies.

Collectively, these observations emphasize a more general importance of the PLAG1 gene in tumour development.

In light of the fact that IGF-IR is implicated in many human tumours, the diversity in PLAG1-induced mouse tumour models, most of which seem to involve Igf2 signaling, provides useful in vivo platforms to start testing the effects of inhibitors, such as Igf-1r inhibitors, on tumour development in distinct tissues or organ types.

Open references

- PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry. Martins C, Fonseca I, Roque L, Pereira T, Ribeiro C, Bullerdiek J, Soares J. Mod Pathol. 2005 Aug;18(8):1048-55. PMID: #15920557# [Free]

- PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, Kozakewich HP, Fletcher JA. Am J Pathol. 2001 Sep;159(3):955-62. PMID: #11549588# [Free]

References

- PLAG1 expression in cutaneous mixed tumors: an immunohistochemical and molecular genetic study. Matsuyama A, Hisaoka M, Hashimoto H. Virchows Arch. 2011 Sep 17. PMID: #21927843#

- Lipoblastoma (LPB): a clinicopathologic and immunohistochemical analysis of 59 cases. Coffin CM, Lowichik A, Putnam A. Am J Surg Pathol. 2009 Nov;33(11):1705-12. PMID: #19738456#

- Van Dyck F, Declercq J, Braem CV, Van de Ven WJ. PLAG1, the prototype of the PLAG gene family: versatility in tumour development (review). Int J Oncol. 2007 Apr;30(4):765-74. Review. PMID: #17332914#

- Zatkova A, Rouillard JM, Hartmann W, Lamb BJ, Kuick R, Eckart M, von Schweinitz D, Koch A, Fonatsch C, Pietsch T, Hanash SM, Wimmer K. Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosomes Cancer. 2004 Feb;39(2):126-37. PMID: #14695992#

- Zheng G, Yang YC. Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. J Biol Chem. 2005 Dec 9;280(49):40773-81. PMID: #16207715#

- Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Zatkova A, Rouillard JM, Hartmann W, Lamb BJ, Kuick R, Eckart M, von Schweinitz D, Koch A, Fonatsch C, Pietsch T, Hanash SM, Wimmer K. Genes Chromosomes Cancer. 2004 Feb;39(2):126-37. PMID: #14695992#

- Landrette SF, Kuo YH, Hensen K, Barjesteh van Waalwijk van Doorn-Khosrovani S, Perrat PN, Van de Ven WJ, Delwel R, Castilla LH. Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood. 2005 Apr 1;105(7):2900-7. PMID: #15585652#

- Kas K, Voz ML, Roijer E, Astrom AK, Meyen E, Stenman G, Van de Ven WJ. Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat Genet. 1997 Feb;15(2):170-4. PMID: #9020842#

- Asp J, Persson F, Kost-Alimova M, Stenman G. CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas. Genes Chromosomes Cancer. 2006 Sep;45(9):820-8. PMID: #16736500#

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