Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human pleomorphic adenoma gene 1 (PLAG1), a developmentally regulated proto-oncogene, is consistently rearranged and overexpressed in pleomorphic salivary gland adenomas and lipoblastomas with 8q12 translocations. Together with PLAGL1 and PLAGL2, PLAG1 belongs to a subfamily of C(2)H(2) zinc finger transcription factors that activate transcription through binding to the bipartite consensus sequence GRGGC(N)(6-8)GGG. Ectopic expression of PLAG1 deregulates target genes and presumably results in uncontrolled cell proliferation. To gain insight into molecular mechanisms regulating PLAG transcriptional capacity, we searched for interaction partners using the yeast two-hybrid system and confirmed these by glutathione S-transferase pull-down. Ubiquitin-conjugating enzyme 9 (UBC9) and protein inhibitor of activated STAT (PIAS) proteins were first identified as genuine interacting partners of mouse PlagL2. Because UBC9 and PIAS are components of the small ubiquitin-related modifier (SUMO) modification pathway, we hypothesized that PLAG proteins could be SUMOylated. Here, we report results obtained for founding family member PLAG1. Its endogenous SUMOylation was demonstrated, and SUMOylation of PLAG1 was further investigated in cells co-transfected with PLAG1 and SUMO-1 DNA or a SUMO-1 mutant form and similarly examined in the presence or absence of DNA encoding the various PIAS proteins. Using anti-PLAG1 antibodies, we discovered single and double SUMO-1-modified forms of PLAG1. By mutating predicted SUMO consensus sites, we defined two important target lysines for SUMOylation in PLAG1, Lys-244 and Lys-263. Moreover, mutation of both SUMO consensus sequences, resulting in inhibition of SUMOylation, led to a significant increase of the transactivation capacity of PLAG1. Nuclear distribution of PLAG1 was not measurably influenced. Our results suggest a direct repression of the transactivating capacity of the oncoprotein PLAG1 by SUMOylation.
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PMID:Repression of the Transactivating Capacity of the Oncoprotein PLAG1 by SUMOylation. 1520 21

Expression of surfactant protein (SP)-C occurs principally in type II pneumocytes located in the distal lung alveolae. SP-C expression is thought to be primarily regulated by thyroid transcription factor (TTF)-1 and its associated proteins interacting with a previously defined promoter region between -197 and -158 in mice. We screened a human lung cDNA library using a modified yeast one-hybrid system and identified pleiomorphic adenoma gene-like (PLAGL)-2, a ubiquitously expressed zinc finger protein, as a transfactor of the SP-C promoter. The PLAGL2 DNA-binding site was located in the SP-C promoter proximal region close to the TTF-1 sites. This site was demonstrated to be functional by use of electrophoresis mobility shift assay, mutagenesis analysis, and transfection studies. PLAGL2 bound to DNA via its N-terminus zinc fingers and activated the SP-C promoter in a TTF-1-independent manner. Both human and mouse SP-C promoters, but not the SP-B promoter, could be activated by PLAGL2 in transfected human embryonic kidney-293 (HEK293) cells as well as in murine type II (MLE12) cells. The expression of PLAGL2 in isolated human embryonic lung type II cells and its transactivation activity on the SP-C promoter suggest that PLAGL2 may modulate SP-C expression during lung development.
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PMID:Pleiomorphic adenoma gene-like-2, a zinc finger protein, transactivates the surfactant protein-C promoter. 1536 64

PLAG1 (pleomorphic adenoma gene 1) and PLAGL2 (PLAG-like 2) are oncogenes involved in various malignancies. Thus the study of their regulatory mechanisms may lead to identification of novel therapeutic targets. In this study, we provide supporting evidence that sumoylation and acetylation regulate functions of PLAG1 and PLAGL2. A conserved transcriptional repression domain exists in both PLAG1 and PLAGL2, whose activity depends on the presence of three sumoylation motifs and an intact sumoylation pathway. In vivo sumoylation assays confirmed that lysines 244, 263, and 353 of PLAG1 and lysines 250, 269, and 356 of PLAGL2 are indeed sumoylation sites. Further study showed that sumoylation inhibits PLAG1-induced IGF-II expression in reporter assays. The repression mediated by sumoylation may be partially explained by its effect on the cellular localization of PLAG1 and PLAGL2, because sumoylation-deficient but not wild-type PLAG1 and PLAGL2 concentrate in the nucleolus. PLAG1 and PLAGL2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by HDAC7. Interestingly, the sumoylation-deficient mutant of PLAGL2 is acetylated at a lower level than its wild-type counterpart, suggesting that some of the lysine residues may be targets for both modifications. Finally, mutation of three lysine residues in sumoylation motifs significantly impairs the transformation ability of PLAG1 and PLAGL2, suggesting the essential roles of these sites in the oncogenic potential of PLAG proteins. Taken together, the activities of PLAG1 and PLAGL2 are tightly modulated by both sumoylation and acetylation, which have opposite effects on their transactivation. To our knowledge, this is the first demonstration that oncoproteins can be regulated by both sumoylation and acetylation.
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PMID:Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. 1620 15

Pleiomorphic adenoma gene (PLAG) family proteins are oncogenes involved in various malignancies including lipoblastomas, hepatoblastomas, and acute myeloid leukemia. Overexpression of PLAGL2 induces cell transformation and proliferation, but little is known about how its activities are regulated. We previously showed that transcriptional activity of PLAGL2 is negatively regulated by sumoylation. Here we report that Tip60 modulates PLAGL2 functions through acetylation. Tip60 associates with PLAGL2 through its zinc finger domain and acetylates PLAGL2. Wild-type but not the histone acetyltransferase (HAT)-minus mutant form of Tip60 enhances PLAGL2-mediated transactivation. In addition, coexpression of Tip60 and PLAGL2 completely abolishes the sumoylation of PLAGL2. Both Tip60 and DN-Ubc9 increase transactivation activity of wild-type but not the sumoylation deficient form of PLAGL2 (K250, 269, 356R), indicating that Tip60 acetylates PLAGL2 and abolishes the sumoylation of PLAGL2 possibly through modification of the same lysine residues (K250, 269, 356) within PLAGL2. Tip60 effects vary between different PLAGL2 target gene promoters, suggesting that Tip60 is a novel promoter-specific coactivator of PLAGL2. This is the first demonstration that Tip60 can function as a sumoylation inhibitor in part through its intrinsic acetyltransferase activity to regulate specific gene expression.
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PMID:Tip60 modulates PLAGL2-mediated transactivation by acetylation. 1755 69

The pleomorphic adenoma gene (PLAG) family of transcription factors regulates a wide range of physiological processes, including cell proliferation, tissue-specific gene regulation, and embryonic development, although little is known regarding the mechanisms that regulate PLAG protein activity. In this study, a yeast two-hybrid screen identified PC2, a component of the Mediator complex, as a PLAGL2-binding protein. We show that PC2 cooperates with PLAGL2 and PU.1 to enhance the activity of a known PLAGL2 target promoter (NCF2). The PLAGL2-binding element in the NCF2 promoter consisted of the core sequence of the bipartite PLAG1 consensus site, but lacked the G-cluster motif, and was recognized by PLAGL2 zinc fingers 5 and 6. Promoter and PLAGL2 mutants showed that PLAGL2 and PU.1 were required to bind to their respective sites in the promoter, and PC2 knockdown demonstrated that PC2 was essential for enhanced promoter activity. Co-immunoprecipitation and promoter-reporter studies reveal that the effect of PC2 on PLAGL2 target promoter activity was conferred via the C-terminus of PLAGL2, the region that is required for PC2 binding and contains the PLAGL2 activation domain. Importantly, chromatin immunoprecipitation analysis and PC2 knockdown studies confirmed that endogenous PC2 protein associated with the NCF2 promoter in MM1 cells in the region occupied by PLAGL2, and was required for PLAGL2 target promoter activity in TNF-alpha-treated MM1 cells, respectively. Lastly, the expression of another known PLAGL2 target gene, insulin-like growth factor II (IGF-II), was greatly diminished in the presence of PC2 siRNA. Together, the data identify PC2 as a novel PLAGL2-binding protein and important mediator of PLAGL2 transactivation.
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PMID:Modulation of PLAGL2 transactivation by positive cofactor 2 (PC2), a component of the ARC/Mediator complex. 2002 40