PhD Student, La Trobe University
To investigate the role that this gene has to play in adult mouse brain
The pleomorphic adenoma gene 1 (Plag1) encodes a transcription factor that is commonly known for its role in certain types of cancer. However, its physiological role has not been properly investigated. Through the use of staining techniques, we were able to find which cells were expressing this gene to get an idea of its role in the brain. Mice lacking the Plag1 gene went through behavioural testing and we found that the Plag1 deficient mice have deafness and female mice in particular have anxiety-like behaviour.
Abstract: Pleomorphic adenoma is the most common benign tumor of the salivary glands. It has marked histological diversity with epithelial, myoepithelial and mesenchymal-type cells arranged in a variety of architectural and differentiation patterns. Pleomorphic adenoma gene 1 (PLAG1), shown to be consistently rearranged in pleomorphic adenomas, is activated by chromosomal translocations involving 8q12, the chromosome region that is most frequently affected in these tumors. In this study, we evaluated PLAG1 involvement in salivary gland tumorigenesis by determining the frequency of its alterations in a selected group of 20 salivary gland tumors: 16 pleomorphic adenomas and four carcinomas ex-pleomorphic adenoma, having in common the presence of karyotypic chromosome 8 deviations, either structural, with 8q12 rearrangements, or numerical, with gain of chromosome 8. PLAG1 status was analyzed using in situ hybridization techniques, on metaphase cells, by fluorescence detection and/or interphase cells in paraffin sections, by chromogenic detection. Except for one pleomorphic adenoma case (5%) that lacked PLAG1 involvement, 17 tumors (85%), (14 pleomorphic adenomas and three carcinomas ex-pleomorphic adenoma) showed intragenic rearrangements of PLAG1 and the remaining two cases (10%), (one pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma), had chromosome trisomy 8 only. To further investigate the role of PLAG1 on pleomorphic adenomas tumorigenesis, as well as the putative morphogenesis mechanism, we attempted to identify the cell types (epithelial vs myoepithelial) carrying 8q12/PLAG1 abnormalities by a combined phenotypic/genotypic analysis in four cases (three pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma) characterized by 8q12 translocations and PLAG1 rearrangement. In these cases, both cells populations carried PLAG1 rearrangements. This finding further supports the pluripotent single-cell theory, which postulates that the tumor-initiated, modified myoepithelial cell, evolves into the varied somatic cell phenotypes present in pleomorphic adenoma, and reinforces the role of PLAG1 on the tumorigenesis of benign and malignant pleomorphic adenoma.
Pub.: 28 May '05, Pinned: 28 Jul '17
Abstract: PLAG1 proto-oncogene overexpression has been causally linked to multiple tumors, highlighting its broad tumorigenic relevance. Here, the oncogenic potential of PLAG1 in mammary gland tumorigenesis was investigated in PLAG1 transgenic mice. To target mammary glands, mice of 2 independent PLAG1 transgenic strains, PTMS1 and PTMS2, in which PLAG1 expression can be modulated by Cre-mediation, were crossed with MMTV-Cre transgenic mice, resulting in P1-MCre and P2-MCre offspring, respectively. Hundred percentage of P1-MCre female mice showed mammary gland hyperplasia, caused by adenomyoepithelial adenosis, at 8 weeks. The tumorigenic process could not be studied further in P1-MCre mice, because concomitant fast-growing salivary gland tumors required euthanasia. Sixteen percentage of P2-MCre females developed mammary gland adenomyoepitheliomas within 30-45 weeks, and none displayed concomitant salivary gland tumors. To further study mammary gland tumorigenesis in PTMS1-derived mice, intercrossing with WAP-Cre transgenic mice, resulting in P1-WAPCre mice, was performed to target PLAG1 expression more specifically to mammary glands. Eighty percentage of such mice developed adenomyoepitheliomas within 53-88 weeks. All PLAG1-induced adenomyoepitheliomas revealed expression upregulation of Igf2/H19, Dlk1/Gtl2, Igfbps and Wnt signaling genes (Wnt6, Cyclin D1). Collectively, these results establish the oncogenic potential of PLAG1 in mammary glands of mice and point towards contributing roles of Igf and Wnt signaling.
Pub.: 24 Jul '08, Pinned: 28 Jul '17
Abstract: PLAG1 is a proto-oncogene whose ectopic expression can trigger the development of pleomorphic adenomas of the salivary glands and of lipoblastomas. 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. The identification of PLAG1 target genes is therefore a crucial step in understanding the molecular mechanisms involved in PLAG1-induced tumorigenesis. To this end, we analysed the changes in gene expression caused by the conditional induction of PLAG1 expression in fetal kidney 293 cell lines. Using oligonucleotide microarray analyses of about 12 000 genes, we consistently identified 47 genes induced and 12 genes repressed by PLAG1. One of the largest classes identified as upregulated PLAG1 targets consists of growth factors such as the insulin-like growth factor II and the cytokine-like factor 1. The in silico search for PLAG1 consensus sequences in the promoter of the upregulated genes reveals that a large proportion of them harbor several copies of the PLAG1-binding motif, suggesting that they represent direct PLAG1 targets. Our approach was complemented by the comparison of the expression profiles of pleomorphic adenomas induced by PLAG1 versus normal salivary glands. Concordance between these two sets of experiments pinpointed 12 genes that were significantly and consistently upregulated in pleomorphic adenomas and in PLAG1-expressing cells, identifying them as putative PLAG1 targets in these tumors.
Pub.: 09 Jan '04, Pinned: 28 Jul '17
Abstract: Pleomorphic adenoma gene 1 (PLAG1) belongs to the PLAG family of zinc finger transcription factors along with PLAG-like 1 and PLAG-like 2. The PLAG1 gene is best known as an oncogene associated with certain types of cancer, most notably pleomorphic adenomas of the salivary gland. While the mechanisms of PLAG1-induced tumorigenesis are reasonably well understood, the role of PLAG1 in normal physiology is less clear. It is known that PLAG1 is involved in cell proliferation by directly regulating a wide array of target genes, including a number of growth factors such as insulin-like growth factor 2. This is likely to be a central mode of action for PLAG1 both in embryonic development and in cancer. The phenotype of Plag1 knockout mice suggests an important role for PLAG1 also in postnatal growth and reproduction, as PLAG1 deficiency causes growth retardation and reduced fertility. A role for PLAG1 in growth and reproduction is further corroborated by genome-wide association studies in humans and domestic animals in which polymorphisms in the PLAG1 genomic region are associated with body growth and reproductive traits. Here we review the current evidence for PLAG1 as a regulator of growth and fertility and discuss possible endocrine mechanisms involved.
Pub.: 19 Nov '15, Pinned: 28 Jul '17
Abstract: Pleomorphic adenoma gene 1 (PLAG1) proto-oncogene overexpression is implicated in various human neoplasias, including salivary gland pleomorphic adenomas. To further assess the oncogenic capacity of PLAG1, two independent PLAG1 transgenic mouse strains were established, PTMS1 and PTMS2, in which activation of PLAG1 overexpression is Cre mediated. Crossbreeding of PTMS1 or PTMS2 mice with MMTV-Cre transgenic mice was done to target PLAG1 overexpression to salivary and mammary glands, in the P1-Mcre/P2-Mcre offspring. With a prevalence of 100% and 6%, respectively, P1-Mcre and P2-Mcre mice developed salivary gland tumors displaying various pleomorphic adenoma features. Moreover, histopathologic analysis of salivary glands of 1-week-old P1-Mcre mice pointed at early tumoral stages in epithelial structures. Malignant characteristics in the salivary gland tumors and frequent lung metastases were found in older tumor-bearing mice. PLAG1 overexpression was shown in all tumors, including early tumoral stages. The tumors revealed an up-regulation of the expression of two distinct, imprinted gene clusters (i.e., Igf2/H19 and Dlk1/Gtl2). With a latency period of about 1 year, 8% of the P2-Mcre mice developed mammary gland tumors displaying similar histopathologic features as the salivary gland tumors. In conclusion, our results establish the strong and apparently direct in vivo tumorigenic capacity of PLAG1 and indicate that the transgenic mice constitute a valuable model for pleomorphic salivary gland tumorigenesis and potentially for other glands as well.
Pub.: 03 Jun '05, Pinned: 28 Jul '17
Abstract: The pleomorphic adenoma gene 1 (Plag1) proto-oncogene encodes a transcription factor and is implicated in human tumorigenesis via ectopic overexpression. No information is available about its developmental role. To address this, a Plag1-/- mouse strain was generated and it appears that Plag1-deficient mice are viable. No anatomical differences are obvious at birth, except that the weight of Plag1-/- mice is significantly lower in comparison to control litter mates. This early growth retardation is maintained throughout adult life with proportionally smaller organs except for the disproportionally small seminal vesicles and ventral prostate; however, plasma testosterone levels in males were not affected. Furthermore, fertility of both male and female Plag1-/- is reduced. Northern blot analysis revealed that Plag1 is developmentally regulated with high overall fetal expression levels, which drop after birth. Furthermore, Plag1 is differentially expressed and is readily detectable in the reproductive organs and pituitary. Expression of growth regulatory Igf2, a known target gene of Plag1 in tumorigenesis, was not affected in Plag1-/- embryos and pups. The general morphology and histology of the size-reduced pituitaries was not affected. Our results establish that Plag1 disruption in mouse differentially affects pre- and postnatal growth and development of organs, with reproductive repercussions.
Pub.: 21 Dec '04, Pinned: 28 Jul '17