Disease relevance of PEG3

• Tumour suppressor activity of human imprinted gene PEG3 in a glioma cell line [1].
• In the eight ovarian cancer cell lines, five were found to be PEG3 negative, the remaining three express low levels of PEG3 mRNA [2].
• In contrast, loss of maternal imprinting and relatively high PEG3 expression levels were detected in all four choriocarcinomas cell lines studied [2].
• We analyzed the PEG3 gene for mutations in women with familial recurrent hydatidiform moles and to determine its imprinting status in humans [3].
• Parental 19q loss and PEG3 expression in oligodendrogliomas [4].

High impact information on PEG3

• We conclude that Peg3 is a regulator of the TNF response [5].
• Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway [6].
• The promoter of PEG-3, PEG-Prom, displays robust expression in a broad spectrum of human cancer cell lines with marginal expression in normal cellular counterparts [7].
• Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression [7].
• Cancer cell selective tropism was ensured by engineering the expression of the adenoviral E1A protein, necessary for viral replication, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells [8].

Chemical compound and disease context of PEG3

• In addition, treatment of glioma cell lines with the DNA demethylating agent 5-aza-2'-deoxycytidine reversed the silencing of PEG3 biallelically [9].

Biological context of PEG3

• Furthermore, in vitro differentiation of the uninduced blastema leads to rapid down-regulation of PEG3, DLK1, and MEIS1 [10].
• Human ZIM2 and PEG3 share a set of 5' exons and a common promoter, and both genes are paternally expressed [11].
• We have identified a novel human gene, ZIM2 (zinc-finger gene 2 from imprinted domain), located 25 kb downstream of PEG3 (paternally expressed gene 3) [12].
• Sequencing of the 5'-termini of both transcripts indicates that ZIM2 and PEG3 share identical transcription start sites and may also share upstream regulatory elements, although the two genes show distinct patterns of tissue-specific expression [12].
• Alternative splicing events connect these 7 exons either with the remaining 2 exons of PEG3 or with the remaining 4 exons of ZIM2 [12].

Anatomical context of PEG3

• We have demonstrated high levels of PEG3 in the human placenta and have localized the signal to the layer of villous cytotrophoblast cells [13].
• In the present study we have investigated the pattern of expression of the human PEG3 gene in the early to term placenta, as well as the uterus and ovary, using RT-PCR, northern blot and in situ hybridization [13].
• The PEG3 promoter is encompassed within a large CpG-rich region that is differentially methylated in fetal tissues [14].
• Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria [15].
• Progression Elevated Gene-3 (PEG-3) was cloned using subtraction hybridization as an upregulated transcript associated with transformation and tumor progression of rat embryo fibroblast cells [16].

Associations of PEG3 with chemical compounds

• The PEG-3 gene is transcriptionally activated in rodent cells, as is gadd34 and MyD116, after treatment with DNA damaging agents, including methyl methanesulfonate and gamma-irradiation [17].
• Treatment of CypA-KD P19 cells with the DNA demethylating agent 5-aza-dC reversed the silencing of Peg3 biallelically [18].
• Genomic bisulfite sequencing and methylation-specific PCR revealed DNA hypermethylation in CypA-KD P19 cells, as the normally unmethylated paternal allele acquired methylation that resulted in biallelic methylation of Peg3 [18].
• Chromatin immunoprecipitation assays indicated a loss of acetylation and a gain of lysine 9 trimethylation in histone 3, as well as enhanced DNA methyltransferase 1 and MBD2 binding on the cytosine-guanine dinucleotide (CpG) islands of Peg3 [18].
• However, the combination therapy was statistically significantly superior to fluticasone propionate alone for mean morning PEFR (P<0.001) and other measures of lung function, whilst clinical equivalence of the combination and concurrent therapies was observed [19].

Regulatory relationships of PEG3

• Furthermore, transient ectopic expression of PEG-3 transcriptionally activates VEGF in transformed rodent and human cancer cells [20].

Other interactions of PEG3

• These observations are striking in light of the structural and functional conservation that typifies other imprinted domains and suggest that the PEG3/ZIM2 imprinted domain may have evolved in an unusual lineage-specific pattern [11].
• Given the known role of PEG3 in p53-mediated apoptosis, it is possible that PEG3 functions as a tumor suppressor [2].
• Increase in the activities of the caspases was observed with up-regulation in the expression of FAS (6-8-fold) and PEG3 (2.5-fold), suggesting that the cells experienced apoptotic cell death via both the death receptor and mitochondrial pathways [21].
• Comparison between mouse Peg3 and partial human PEG3 gene sequences revealed a high level of conservation between the two species, despite the fact that one of the two proline-rich repeats is absent from the human gene [22].
• Moreover, c-myc, PEG-3, VEGF, and TNFA were also expressed strongly in the glial cells or extra-cellular spaces in the area of peri-tumoural oedema [23].

Analytical, diagnostic and therapeutic context of PEG3

• METHODS: PEG3 mRNA levels were measured with real-time PCR from 28 gynecologic cancer cell lines and compared to normal tissues [2].
• Sequence analysis of the rat Gadd34 gene and comparison with PEG-3 indicates that PEG-3 is most likely a mutant of Gadd34 that perhaps arose as a result of transformation [24].

References