Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen receptor (AR) binds to and activates transcription of specific genes in response to its cognate steroid hormone, dihydrotestosterone. Transcriptional activation by the DNA-bound AR is accomplished with the help of a variety of coactivator proteins. For example, the p160 coactivators bind directly to AR and recruit additional coactivators such as the histone acetyltransferase p300 and the histone methyltransferase CARM1. The current study tested whether CARM1 can cooperate with other types of coactivator proteins. Recently it was shown that beta-catenin can also bind directly to and serve as a coactivator for AR. Here it is shown that CARM1 binds to beta-catenin and can function in synergy with beta-catenin and p300 as coactivators for AR. The methyltransferase activity of CARM1 is important for its synergistic coactivator function with beta-catenin. The synergistic coactivator function of beta-catenin and CARM1 is not restricted to steroid receptors because these two coactivators can also act synergistically with another type of DNA binding transcriptional activator, LEF-1/TCF-4.
 ...
PMID:Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators. 1198 85

beta-Catenin, a pivotal component of the Wnt-signaling pathway, binds to and serves as a transcriptional coactivator for the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcriptional activator proteins and for the androgen receptor (AR), a nuclear receptor. Three components of the p160 nuclear receptor coactivator complex, including CARM1, p300/CBP, and GRIP1 (one of the p160 coactivators), bind to and cooperate with beta-catenin to enhance transcriptional activation by TCF/LEF and AR. Here we report that another component of the p160 nuclear receptor coactivator complex, the coiled-coil coactivator (CoCoA), directly binds to and cooperates synergistically with beta-catenin as a coactivator for AR and TCF/LEF. CoCoA uses different domains to bind GRIP1 and beta-catenin, and it uses different domains to transmit the activating signal to the transcription machinery, depending on whether it is bound to GRIP1 or beta-catenin. CoCoA associated specifically with the promoters of transiently transfected and endogenous target genes of TCF/LEF, and reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin to activate transcription of transient and endogenous target genes. Thus, CoCoA uses different combinations of functional domains to serve as a physiologically relevant component of the Wnt/beta-catenin signaling pathway and the androgen signaling pathway.
 ...
PMID:Differential use of functional domains by coiled-coil coactivator in its synergistic coactivator function with beta-catenin or GRIP1. 1634 50

The underlying molecular mechanisms of tumorigenesis and progression of non-small cell lung cancer (NSCLC) are not yet fully elucidated. In the present study, in vitro functional dissections suggest that siRNA-mediated silencing of CCNE2 profoundly attenuated the proliferative and colony-formative abilities of NSCLC PC9 and HCC827 cells, while forced overexpression of CCNE2 significantly strengthened the proliferative and colony-formative capabilities of these cells. Intriguingly, by ChIP and luciferase reporter gene assays, we observed that CARM1 is recruited to the promoter regions of CCNE2 gene and acts as a transcriptional activator. Mechanically, the asymmetric di-methylation of H3R17me2a and H3R26me2a, as the catalytic substrates of CARM1, were highly enriched at the core promoter regions of CCNE2 gene, thereby activating the expression of CCNE2. In vitro and in vivo rescue experiments demonstrated that restoration of CCNE2 expression significantly abolished the CARM1 shRNA-mediated inhibition of cell proliferation, indicating that the oncogenic function of CARM1, at least partially, depended on the activation of CCNE2. Inhibition of CARM1 enzymatic activity could significantly repress CCNE2 expression in NSCLC cells. In addition, the expression of CARM1 was significantly elevated and positively correlated with CCNE2 levels in 20 cases of NSCLC patients. Both CARM1 and CCNE2 are highly associated with shorter 10-year overall survival of at a large cohort of 461 cases of NSCLC patients from the Kaplan-Meier plotter database. To summarize, these findings provide compelling evidence that CARM1 could promote NSCLC progression via activation of CCNE2, paving the way for future therapeutic strategies in NSCLC.
 ...
PMID:CARM1 promotes non-small cell lung cancer progression through upregulating CCNE2 expression. 3248 79