Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurons withdraw from the cell cycle immediately after differentiation from their proliferative precursors. E2F1, a principal transcription factor that promotes cell cycle progression, must be silenced in neurons. We investigated the E2F1 system in postmitotic neurons derived from murine embryonal carcinoma P19 cells. P19 cells highly expressed the E2F1 gene during neural differentiation, and enriched neurons contained a high abundance of E2F1 mRNA. In contrast, postmitotic neurons possessed extremely low levels of E2F1 protein as assessed by the electrophoretic mobility shift assay and Western blotting. A recombinant E2F1 fusion protein was ubiquitinated in vitro when incubated with neuronal lysates. In addition, treatment with the proteasome inhibitor MG132 increased the endogenous level of E2F1 protein in neurons. These results suggest that the ubiquitin-proteasome pathway contributes, at least in part, to the downregulation of E2F1 protein in postmitotic neurons. Adenovirus-mediated transfer of E2F1 cDNA into postmitotic neurons induced both bromodeoxyuridine incorporation and chromatin condensation, suggesting that deregulated E2F1 expression causes both aberrant S-phase entry and apoptosis of postmitotic neurons. Thus, downregulation of endogenous E2F1 protein in postmitotic neurons may be indispensable for the prevention of their reentry into the cell cycle.
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PMID:Regulation and deregulation of E2F1 in postmitotic neurons differentiated from embryonal carcinoma P19 cells. 1047 29

The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 induces cell proliferation. In addition, E2F1 can induce apoptosis via both p53-dependent and p53-independent pathways. A number of E2F-regulated genes, including ARF, ATM and Chk2, contribute to E2F-induced p53 stabilization. However, it is not known how E2F directs p53 activity towards apoptosis rather than growth arrest. We show that E2F1 upregulates the expression of four proapoptotic cofactors of p53--ASPP1, ASPP2, JMY and TP53INP1--through a direct transcriptional mechanism. Adenovirus E1A protein also induces upregulation of these genes, implicating endogenous E2F in this effect. TP53INP1 was shown to mediate phosphorylation of p53 on serine 46. We demonstrate that activation of E2F1 leads to phosphorylation of p53 on serine 46 and this modification is important for E2F1-p53 cooperation in apoptosis. Overall, these data provide novel functional links between RB/E2F pathway and p53-induced apoptosis.
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PMID:Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. 1570 52

Proliferation of mammalian cardiomyocytes ceases around birth when a transition from hyperplastic to hypertrophic myocardial growth occurs. Previous studies demonstrated that directed expression of the transcription factor E2F1 induces S-phase entry in cardiomyocytes along with stimulation of programmed cell death. Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression. Although both E2F2 and E2F4 induced S-phase entry only directed expression of E2F2 resulted in mitotic cell division of cardiomyocytes. Expression of E2F5 or a control LacZ-Adenovirus had no effects on cell cycle progression. Quantitative real time PCR revealed that E2F1, E2F2, E2F3, and E2F4 alleviate G0 arrest by induction of cyclinA and E cyclins. Furthermore, directed expression of E2F1, E2F3, and E2F5 led to a transcriptional activation of several proapoptotic genes, which were mitigated by E2F2 and E2F4. Our finding that expression of E2F2 induces cell division of cardiomyocytes along with a suppression of proapoptotic genes might open a new access to improve the regenerative capacity of cardiomyocytes.
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PMID:Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis. 1571 99

Small nuclear ribonucleoproteins are essential splicing factors. We previously identified the spliceosomal protein E (SmE) as a downstream effector of E2F1 in p53-deficient human carcinoma cells. Here, we investigated the biological relevance of SmE in determining the fate of cancer and non-tumourigenic cells. Adenovirus-mediated expression of SmE selectively reduces growth of cancerous cells due to decreased cell proliferation but not apoptosis. A similar growth inhibitory effect for SmD1 suggests that this is a general function of Sm-family members. Deletion of Sm-motifs reveals the importance of the Sm-1 domain for growth suppression. Consistently, SmE overexpression leads to inhibition of DNA synthesis and G2 arrest as shown by BrdU-incorporation and MPM2-staining. Real-time RT-PCR and immunoblotting showed that growth arrest by SmE directly correlates with the reduction of cyclin E, CDK2, CDC25C and CDC2 expression, and up-regulation of p27Kip. Importantly, SmE activity was not associated with enhanced expression of other spliceosome components such as U1 SnRNP70, suggesting that the growth inhibitory effect of SmE is distinct from its pre-mRNA splicing function. Furthermore, specific inactivation of SmE by shRNA significantly increased the percentage of cells in S phase, whereas the amount of G2/M arrested cells was reduced. Our data provide evidence that Sm proteins function as suppressors of tumour cell growth and may have major implications as cancer therapeutics.
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PMID:Spliceosomal protein E regulates neoplastic cell growth by modulating expression of cyclin E/CDK2 and G2/M checkpoint proteins. 1820 61

Adenovirus E1A oncogene transforms primary rodent fibroblasts in cooperation with activated Ras. Conversely, the c-Myc oncoprotein-binding tumor suppressor, Bin1, inhibits Ras/E1A-mediated cell transformation. Since E1A does not directly bind to and inhibit Bin1, the primary mechanism by which E1A counteracts Bin1 to liberate oncogenic c-Myc activity is poorly understood. Here we show that wild-type E1A, but not an Rb binding-defective E1A mutant, suppresses endogenous Bin1 expression in cultured rodent fibroblasts. Similarly, other anti-Rb agents, such as human papillomavirus E7, mitogenic stimuli, and small interfering RNA (siRNA) for Rb, consistently decrease Bin1 promoter activity. In contrast, serum starvation, which activates Rb, enhances endogenous Bin1 levels. These findings suggest that Bin1 may be a novel component of Rb-mediated G1 arrest. Consistent with this premise, chromatin immunoprecipitation assays demonstrate that Rb protein directly interacts with the Bin1 promoter only upon removal of serum. Furthermore, ectopically expressed E2F1, which is primarily inhibited by Rb under serum-starved condition, represses Bin1 promoter activity in a manner that is dependent on the DNA-binding and transactivation domains of E2F1. Lastly, depletion of endogenous Bin1 per se is biologically meaningful since antisense or siRNA of Bin1 transfection releases endogenous c-Myc transcriptional activity and, concomitantly, accelerates cell proliferation. Our results suggest that Bin1 gene suppression caused by oncogenic E1A via Rb inactivation is an essential step in cell cycle progression promoted by c-Myc, and subsequently, E1A transformation. We propose a novel G1 arrest signaling mechanism by which Rb indirectly curbs oncogenic c-Myc activity via sustaining Bin1 expression.
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PMID:Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. 1834 66

Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.
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PMID:Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim. 2812 90