Wnt pathway is involved in pleomorphic adenomas induced by overexpression of <i>PLAG1</i> in transgenic mice

Zhao, Xudong; Ren, Weihua; Yang, Wenjun; Wang, Yi; Kong, Hui; Wang, Long; Yan, Lei; Xu, Guangwen; Fei, Jian; Fu, Jian; Zhang, Chenping; Wang, Zhugang

doi:10.1002/ijc.21400

Cited by 41 publications

(39 citation statements)

References 30 publications

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“…To explore the role of PLAG1 in neoplastic transformation in vivo in the context of a complex organism, transgenic mouse strains were developed (2,44). The most versatile strains are conditional transgenics in which activation of overexpression of the PLAG1 transgene as well as the tissue distribution of such overexpression can be manipulated (e.g., by Cre-mediated activation and targeted expression, respectively) (Fig.…”

Section: Oncogenic Capacity Of Plag1 In Vivomentioning

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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Section: Oncogenic Capacity Of Plag1 In Vivomentioning

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

View full text Add to dashboard Cite

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“…Additionally, a recent report has shown that Wnt signaling pathway may be involved in pleomorphic adenomas induced by overexpression of Plag1 in transgenic mice, since these animals exhibited upregulation of b-catenin and c-myc, two major components of the Wnt pathway (Zhao et al, 2006).…”

Section: Role Of Growth Factor Signaling Pathwaymentioning

confidence: 99%

“…Also, recent reports have established a direct in vivo tumorigenic capacity of PLAG1 overexpression in pleomorphic salivary gland tumorigenesis in transgenic mice (Declercq et al, 2005;Zhao et al, 2006). It is believed that Wnt signaling pathway is involved in pleomorphic adenomas induced by overexpression of Plag1 in these transgenic mice, since they showed upregulation of b-catenin and c-myc, two components of the Wnt pathway (Zhao et al, 2006). As was noted above, PLAGL1/LOT1/ZAC1 inhibits proliferation of tumor cells by inducing cell-cycle arrest and apoptosis (Abdollahi et al, 1997a(Abdollahi et al, ,b, 1999Spengler et al, 1997).…”

Section: Gene Expression In Tumors and Cancer Cellsmentioning

confidence: 99%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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Lost-on-transformation 1 (LOT1) (PLAGL1/ZAC1) is a member of the novel subfamily of zinc-finger transcription factors, designated as PLAG family. The other members in this group include PLAG1 and PLAGL2, which share high homology with each other and with LOT1, particularly in their zinc-finger amino-terminal region. They are structurally similar but functionally different. For example, the LOT1 gene encodes a growth suppressor protein and is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancers. The gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus (TNDM). LOT1 is a target of growth factor signaling pathway(s) and silenced by epigenetic mechanisms, as well as by the loss of heterozygosity in different tumor tissues. PLAG1 is a protooncogene that is localized on chromosome 8q12 and was found to be a target of several types of chromosomal rearrangement including the one identified in pleomorphic adenomas of the salivary gland. Since the discovery of the PLAG family members in 1997, much has been learned about their structure and function, as are summarized in this review. While the available data suggest that these proteins may play important roles in regulating normal physiological functions in the mammals, a great deal more about their signaling pathway(s), potential role in the complex pathologies such as cancer and developmental disorders, and functional relationship between different family members and splice variants still remains to be uncovered.

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“…The oncogenic capacity of PLAG1 has been demonstrated in vitro, i.e. in cell lines that were retrovirally transduced with PLAG1 (22), and recently, in vivo in mouse models (23,24). Whereas Zhao and co-workers generated classical, non-conditional transgenic mouse strains (24), we developed two independent PLAG1 transgenic mouse strains, PTMS1 and PTMS2, in which activation of overexpression of the transgene as well as the tissue distribution of such overexpression can be manipulated, by Cre-mediated activation and targeted expression, respectively (23).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Igf and Wnt signalling associated genes in pleomorphic adenomas of the salivary glands in PLAG1 transgenic mice

Declercq

Dyck²,

Damme³

et al. 2008

Int J Oncol

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Abstract. The Pleomorphic adenoma gene 1 (PLAG1) is involved in various human neoplasias, including pleomorphic adenomas of the salivary glands. Moreover, the oncogenic role of PLAG1 was clearly demonstrated in two independent PLAG1 transgenic mouse founders, in which PLAG1 expression could be targeted to different tissues using the Cre/loxP system. MMTV-Cre-mediated targeted overexpression of PLAG1 in the salivary glands of double transgenic offspring mice, referred to as P1-MCre and P2-MCre mice, induced pleomorphic adenomas in this organ. Igf2, a genuine PLAG1 target gene, was highly upregulated in those tumours as well as in human pleomorphic adenomas of the salivary glands. These and previous observations in other PLAG1-induced tumours e.g. breast adenomyoepitheliomas emphasize the importance of Igf upregulation in such tumours. In this study, further evidence for the role of Igf2 in PLAG1-induced tumourigenesis, is reported. Inactivation of Igf2 in P1-MCre mice leads to a significant delay in tumour development. Since tumour development is not fully abrogated by inactivation of Igf2, other signalling pathways are likely to contribute to PLAG1-induced tumourigenesis as well. Further studies revealed that several genes such as H19, Dlk1, Gtl2, Igfbp2, Igfbp3 and genes involved in Wnt signalling, such as Wnt6, Cyclin D1 and ß-catenin are upregulated in P1-MCre mice in which Igf2 is inactivated. In conclusion, we clearly demonstrate upregulation of several genes associated with Igf and Wnt signalling in PLAG1-induced pleomorphic adenomas. Furthermore, inactivation of Igf2 does not affect upregulation of genes associated with Wnt signalling, which might suggest that both signalling pathways are involved.

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

Cited by 41 publications

References 30 publications

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

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

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Upregulation of Igf and Wnt signalling associated genes in pleomorphic adenomas of the salivary glands in PLAG1 transgenic mice

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