Evidence of involvement of the PLAG1 gene in lipoblastomas.

Astrom, A. K.; dʼAmore, Emanuele S.G.; Sainati, Laura; Panarello, Claudio; Morerio, Cristina; Mark, Joachim; Stenman, Göran

doi:10.3892/ijo.16.6.1107

Cited by 48 publications

(42 citation statements)

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“…The second most common participating gene is the leukemia inhibitory factor receptor (LIFR) gene [25]. The molecular mechanisms of PLAG1 alteration in lipoblastoma are similar to those in PA but involve different partner genes, COL1A2 or HAS2 [26,27].…”

Section: Discussionmentioning

confidence: 99%

PLAG1 Alteration in Carcinoma Ex Pleomorphic Adenoma: Immunohistochemical and Fluorescence In Situ Hybridization Studies of 22 Cases

Bahrami

Dalton

Bangalore

et al. 2012

Head and Neck Pathol

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Section: Discussionmentioning

confidence: 99%

PLAG1 Alteration in Carcinoma Ex Pleomorphic Adenoma: Immunohistochemical and Fluorescence In Situ Hybridization Studies of 22 Cases

Bahrami

Dalton

Bangalore

et al. 2012

Head and Neck Pathol

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“…With respect to human tumours, PLAG1 is consistently rearranged, not only in a large subgroup of pleomorphic adenomas of the salivary glands (1,5-7), as discussed above, but also in lipoblastomas (33,34). Lipoblastomas are benign paediatric neoplasias resulting from transformation of adipocytes.…”

Section: Plag1-induced Tumours In Humans and Micementioning

confidence: 99%

PLAG1, the prototype of the PLAG gene family: Versatility in tumour development (Review)

Dyck

Declercq²,

Braem³

et al. 2007

Int J Oncol

100

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Abstract. Recent studies of human tumours as well as genetically engineered mouse tumour models have established the importance and versatility of the PLAG1 oncogene in tumourigenesis. 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. 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. 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. Furthermore, 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. 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. 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.

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“…In addition to pleomorphic adenomas, ectopic expression of PLAG1 is also at least in part responsible for the development of lipoblastomas, 5,6 hepatoblastomas, 7 leiomyomas and leiomyosarcomas. 4 Although the various molecular events, including chromosomal translocations, amplification in specific chromosomal regions and even tumors with normal karyotype were also reported, overexpression of PLAG1 was frequently detected in these tumors.…”

mentioning

confidence: 99%

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

Zhao¹,

Ren²,

Yang³

et al. 2005

Intl Journal of Cancer

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Pleomorphic adenoma gene 1 (PLAG1) was found frequently rearranged and activated in human salivary gland pleomorphic adenomas. It encodes a developmentally regulated transcription factor. Ectopic overexpression of PLAG1 has been proposed to play a crucial role in tumorigenesis of salivary gland pleomorphic adenomas. It was reported that PLAG1 can activate the transcription of insulin-like growth factor 2 (IGF2), functioning as a protooncogene. In this report, we show that the salivary gland tumors developed in PLAG1 transgenic mice share major histopathologic features with human pleomorphic adenomas. It was found that b-catenin, the key component of Wnt signaling pathway, was upregulated at transcriptional level in tumors developed in 3 independent transgenic mouse lines. Immunohistochemical staining revealed that expression of b-catenin as well as c-myc, downstream of b-catenin in Wnt signaling pathway, was highly upregulated with overexpression of PLAG1 transgene in tumor and normal transgenic salivary gland tissues. Moreover, we found that PLAG1 can activate the transcription of mouse but not human b-catenin in the 3T3 cells cotransfected with reporter constructs. Sequence analysis shows there are 4 PLAG1 consensus binding sites in mouse b-catenin promoter region but not in human. Our findings provide the first in vivo evidence for the oncogenic activity of PLAG1 in pleomorphic adenoma tumorigenesis, reveal a valued animal model for human salivary gland tumors and suggest that Wnt signaling pathway may also contribute to the development of pleomorphic adenomas in transgenic mice. ' 2005 Wiley-Liss, Inc.Key words: pleomorphic adenoma gene 1; transgenic mice; b-catenin; pleomorphic adenomas The pleomorphic adenoma is the most common type of salivary gland tumor, which accounts for more than 50% of all salivary gland neoplasms. It usually behaves as the benign slow-growing tumor morphologically characterized by a biphasic pattern containing both epithelial and mesenchymal areas. 1 In recent years, a series of studies on tumorigenesis of salivary gland tumors has revealed that oncogenic activation of pleomorphic adenoma gene 1 (PLAG1) on 8q12 plays a crucial role in the development of pleomorphic adenomas originating from salivary glands. The major form of PLAG1 activation is reciprocal chromosomal translocations that lead to promoter swapping between PLAG1 gene, which is not expressed or weakly expressed in adult salivary glands, and the genes ubiquitously expressed in adult tissues, such as the b-catenin gene on 3p21, 2 the leukemia-inhibitory factor receptor (LIFR) gene on 5p13 and the transcription elongation factor SII gene on 3p21. 3-22. 3,4 The breakpoints of both fusion partner genes invariably occur in the 5 0 noncoding regions and consequently lead to ectopic expression of PLAG1 gene in salivary glands. In fact, the chromosomal translocations involving 8q12 only account for 39% of tumors. Other chromosomal abnormalities were also found to be associated with the formation of pleomorphic adenomas, such ...

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Evidence of involvement of the PLAG1 gene in lipoblastomas.

Cited by 48 publications

References 0 publications

PLAG1 Alteration in Carcinoma Ex Pleomorphic Adenoma: Immunohistochemical and Fluorescence In Situ Hybridization Studies of 22 Cases

PLAG1 Alteration in Carcinoma Ex Pleomorphic Adenoma: Immunohistochemical and Fluorescence In Situ Hybridization Studies of 22 Cases

PLAG1, the prototype of the PLAG gene family: Versatility in tumour development (Review)

Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice

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