The conserved bHLH domain is associated with homo- or hetero-dimerization to form a functional transcriptional unit that binds for the canonical E- Box response element found in the promoter of numerous genes . E2A gene codes for two alternatively spliced transcription factors E12 and E47 . E12 and E47 mainly serve as partners for dimerization with tissue exact bHLH proteins such as MyoD, NeuroD and MASH to promote cell certain differentiation . E2A is regulated mostly at post-transcriptional level via protein-protein interactions: interaction of E2A with dominant adverse HLH proteins, the inhibitor of differentiation family seems for being the primary mechanism that regulates E2A activity . The Id proteins neutralize E2A by HLH mediated dimerization; nonetheless the lack in the standard domain in Id proteins renders the dimer transcriptionally inactive. The HLH domain of E2A also interacts with non-bHLH proteins just like ubiquitin-conjugating enzyme UBC9/UbcE2A and histone acetyl transferases: p300, CBP and PCAF.
The interaction with UBC9 is required for ubiquitination and subsequent proteosomal degradation of E2A . E2A proteins RAD001 also extend the half-life of its main interaction partners, the Id and MyoD proteins . E2A is vital for lymphopoiesis as reveled in E2A null mice . Proof suggests that E2A proteins act as standard detrimental regulator of cell proliferation in many normal cells and cancer cell lines . The growth inhibition by E2A occurs at numerous amounts involving both bHLH dependent and independent mechanisms. Major amongst they’re the transcriptional up-regulation of various cyclin dependent kinase inhibitors CDKN1A , p15INK4B and p16INK4B . Ectopic expression of E2A also promotes apoptosis in E2A deficient lymphomas, independent of an arrest in cell-cycle progression .
Contrary to its well established part as an inhibitor of proliferation, additional hints E2A expression can be observed in cells undergoing quick proliferation from the rat embryo and in proliferating periventricular neuroepithelial cells during the creating brain and in centroblasts inside germinal centers . E2A also promotes epithelial to mesenchymal transitions attributable to direct inhibition of E-cadherin expression on the promoter degree , a mechanism central to cancer progression. In the course of our investigations to understand the mechanism of action of Id proteins in prostate cancer , we observed that E2A expression was very low to negligible in PCa cell line LNCaP but substantial in two aggressive PCa cell lines DU145 and PC3. These preliminary observations prompted us to investigate the association of E2A with PCa.
Information mining demonstrated that E2A expression right correlated with PCa. These observations were validated by E2A immuno-histochemical analysis in PCa specimens on this examine. On the molecular degree, ablation of E2A prospects to apoptosis and G1 arrest dependent proliferation block in PCa cell lines.