E2f1 uses the atm signaling pathway to induce p53 and. This newly discovered activity of deregulated e2f1 reflects a cell contextdependent. The results were suggested that heavy ion ir could induce p53cancer cells apoptosis via e2f1 signal pathway. E2f1 mediated apoptosis is tightly regulated by the rb protein, which efficiently blocks e2f1 mediated apoptosis 32, 33. E2f1 induced apoptosis occurs via multiple pathways. Deregulation of cmyc andor e2f1 protooncogenes is implicated in the development. A double band of the protein of yet, data from microarray analysis suggest the involvement of b55 kd size indicative of increased dip levels was detected proapoptotic bcl2 family members on the p53autonomous as early as 24 h after e2f1 inititiation in both the inducible death pathway. E2f1 mediated apoptosis induced by the dna damage response is. Liu, and qiang yu laboratory of molecular pharmacology, genome institute of singapore, genome building, no. Skp2 suppresses apoptosis in rb1deficient tumours by limiting e2f1 activity. Apr 15, 2002 in addition, it has been shown that the rb pathway is linked to events involved in an antitumor safeguard mechanism through the induction of apoptosis which is largely mediated by e2f1.
Jul 01, 2005 on the basis of previous reports, we envision that increased e2f1 activity leads to apoptosis through an arfp53. Luciferase reporter assay and chromatin immunoprecipitation showed that cdca5 was transcribed by e2f1. Indeed, at variance with those apoptotic pathways in which e2f1 expression is required for their execution, unexpectedly we found that its level decreases during er stressmediated apoptosis and this downregulation importantly contributes to the timeregulated execution of cell death pathway. Here we define a pathway in which deregulation of e2f1 either by ectopic expression of e2f1 or inactivation of retinoblastoma protein rb family members by human papillomavirus type 16 hpv16 e7 signals apoptosis by inducing the expression of chk2. Inhibitors of histone deacetylases target the rb e2f1 pathway for apoptosis induction through activation of proapoptotic protein bim yan zhao, jing tan, li zhuang, xia jiang, edison t.
The development of cancer depends on the delicate balance between cell proliferation and programmed cell death. To determine whether e2f1 induces a signal promoting apoptosis or whether e2f1 induced apoptosis is the result of a lack of a signal promoting cell survival that would be induced by the other e2f members, we have examined the effects of overproduction of e2f1 together with each of the other e2f activities and analyzed the cells for the. E2f1 inhibits cmycdriven apoptosis via pik3caaktmtor and. The e2f family of transcription factors 11 figure 4. Our findings indicate that rb induces autophagy by repressing e2f1 activity. E2f1 death pathways as targets for cancer therapy ncbi nih. Selective induction of e2f1 in response to dna damage, mediated. Here, we describe a novel connection between e2f1 and the atm dna damage response pathway. A recent study reveals epidermal growth factor receptor egfr signaling to be one such variable, as egfr signaling cooperates with rb in inhibiting. Additional pathways mediating e2f1 induced apoptosis the p53 homolog p73 also plays a role in e2f1 induced apoptosis. E2f1 pathways to apoptosis ginsberg 2002 febs letters. Dna microarray analysis reveals unique sets of target promoters among e2f family members suggesting that each protein has a unique role in the cell.
Pdf the e2f family and the role of e2f1 in apoptosis. These results demonstrate a specific role for e2f1, which triggers a pathway leading to arf and p53 induction. In this study, we generated a rb1 lossoffunction zebrafish. Taken together, these results suggest a biological role for the activation of arf expression by. In the p53independent apoptosis pathway, e2f1 directly activated some apoptotic genes, such as p73, the homologous gene of p53, and apoptotic protease activating factor 1 apaf1, thereby activating the proapoptotic effector enzymes caspase3, caspase6, and caspase7 and inducing apoptosis. Rbe2f pathway and cancer human molecular genetics oxford. All of them are involved in the cell cycle regulation and synthesis of dna in mammalian cells. The effects of e2f1 on apoptosis can be regulated by p53. Nucleoprotein of influenza a virus negatively impacts. Both p53 and e2f1 are transcription factors involved in the decision process. E2f1 uses the atm signaling pathway to induce p53 and chk2 phosphorylation and apoptosis john t. Pdf downregulation of e2f1 during er stress is required. E2f is a group of genes that encodes a family of transcription factors tf in higher eukaryotes.
Research paper cdca5, transcribed by e2f1, promotes. Cdca5, transcribed by e2f1, promotes oncogenesis by enhancing. Jab1 is a specificity factor for e2f1induced apoptosis. One of the possible candidates is the rb e2f1 pathway. A role for e2f1 in the induction of arf, p53, and apoptosis. Several other proteins including cmyc, p53, pka, pkc, nf. It is well documented that the e2f1 transcription factor is a key regulator of apoptotic programs.
E2f1 mediated apoptosis induced by the dna damage response. Upstream signals direct e2f1 to proliferation or apoptosis. Downregulation of e2f1 in cells results in high levels of autophagy. E2f1 in mouse embryonic fibroblasts results in cells entering premature s phase and significant apoptosis 6. Analysis of e2f1 target genes involved in cell cycle and. Although the link between api5 and e2f1 in the apoptosis pathway has been elegantly described 22, it is not. Jan 30, 2007 the extent of e2f1 induced apoptosis is known to be tissue and cellspecific, but until now, it has been unclear what variables determine cellular sensitivity to e2f1 induced apoptosis in vivo. In rbf1null cells, e2f1 activity is elevated but e2f1 induced apoptosis can be prevented by egfrrasraf signaling. E2f1 mediated apoptosis is known to be associated with both p53 dependent and independent mechanisms 4.
The aryl hydrocarbon receptor binds to e2f1 and inhibits e2f1. Downregulation of e2f1 during er stress is required to induce. E2f1 induced apoptosis occurs via multiple pathways, some of which induce stabilization and activation of the tumor suppres sor p53. E2f family members play a major role during the g1s transition in mammalian and plant cell cycle see kegg cell cycle pathway. Expression of apoptosis related molecules in hek293 transfec 7 d. Dec 17, 2015 apoptosis, the major form of programmed cell death, has been implicated in viral disease progression and pathogenesis of many viruses. Resistance to genotoxic drugs is the major cause of cancer therapy failure. E2f1 induced apoptosis is attributed mainly to e2fmediated upregulation of various pro apoptotic genes.
Api5 contributes to e2f1 control of the g1s cell cycle phase. Activation of the rbe2f1 pathway by the nonproliferative p38. Works reported from many other laboratories, including our own, showed that the transcription factor e2f1 is an important mediator of neuronal apoptosis 2631. E2f1 induced apoptosis occurs via multiple pathways, some of which induce stabilization and activation of the tumor suppressor p53. We conclude that e2f family members play distinct roles in cell cycle control and that e2f1 may function as a specific signal for the initiation of an apoptosis pathway that must normally be blocked for a productive proliferation event. Together,ourfindingsdefinethee2fcdc2cellcyclepathwayas a novel and specific mechanism by which activity deprivation induces apoptosis of postmitotic neurons. These results demonstrate a specific role for e2f1, which triggers a pathway. E2f1 promotes apoptosis in several systems, either in association with p53 16, 18 or independent of p53 28, 29. More recent work has shown that e2f 1 regulates apoptosis as well as proliferation, in part by stabilizing the p53 tumor suppressor, an important mediator of apoptosis.
Recently, several studies have described novel networks. As a key member of the e2f family, e2f1 is overexpressed in many cancers including hcc. The interaction between e2f1 and other genes was shown to play a fundamental role in ovarian cancer. Egfr signaling inhibits e2f1induced apoptosis in vivo. These findings suggest that p53 phosphorylation is a key step in e2f1 mediated apoptosis and that this modification can occur in the absence of p19arf. As reported, e2f1 overexpression triggers apoptosis subsequent to s phase entry of quiescent cells. After dna damage, cells must decide between different fates including growth arrest, dna repair, and apoptosis. Thus, if the pathways that mediate e2f1 induced apoptosis are disabled, e2f1 functions strictly as a growth promoter.
Rb binding to e2 transcription factor e2f is required for autophagy induction and e2f1 antagonizes rbinduced autophagy, leading to apoptosis. E2f1 induced apoptosis is significantly reduced by inhibitors of caspase activity or by gene disruption of apafi, indicating that the e2f1 apaficaspases pathway is an important mediator of e2f1 induced apoptosis. Interestingly, e2f1 can also promote cellular apoptosis regardless of p53 status by activating a number of proapoptotic genes in response to dna damage stimuli. B, and cdk have been shown to regulate both cell cycle and apoptosis. E2f6 inhibits cobalt chloridemimetic hypoxiainduced. Overview of signal transduction pathways involved in apoptosis. E2f1 is a transcription factor regulating genes involved in cell cycle and apoptosis ginsberg, 2002, and interestingly mcph1 is involved in transcriptional regulation of several dna repair. Activation of the rbe2f1 pathway by the nonproliferative. Deregulation of the rb e2f1 pathway also results in the activation of p53 and the promotion of apoptosis, and this contributes to the suppression of tumor development. Members of the e2f family of transcription factors play an important role in regulating the cell cycle, and their activity is often perturbed during the development of human malignancies.
Furthermore, we confirmed that cdca5 interrupted cell behavior via the pathway. The e2f1 induced apoptosis was found to be reduced significantly by coexpression of a dominant interfering form of cdc2. The proapoptotic activity of e2f1 suggests that its deregulation constitutes an oncogenic stress that may target premalignant cells to undergo apoptosis, thus preventing tumor development. E2f1 promotes apoptosis viathe tumour suppressor p53 and independent of p53. Rb promotes growth arrest, whereas e2f1 positively regulates the transition from the g 1 to the s phase. Sirt5 promotes cell proliferation and invasion in hepatocellular carcinoma by targeting e2f1. Pdf tfdp3 inhibits e2f1induced, p53mediated apoptosis. Here, we proposed a fourmodule kinetic model of the decision process and explored the interplay between these. E2f1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic. Johnson1,2 1department of carcinogenesis, university of texas md anderson cancer center, science parkresearch division, smithville, texas. The rbe2f1 pathway regulates autophagy cancer research. The e2fcdc2 cellcycle pathway specifically mediates.
These findings suggest that there may be a more intimate relationship between the apoptosis pathways resulting from loss. Cdca5, transcribed by e2f1, promotes oncogenesis by. Cancer research the rbe2f1 pathway regulates autophagy. Examples rbe2f pathway disruptions in human malignancy 7 figure 3. Inhibition of e2f1 with sirna blocks apoptosis induced by loss of ahr. Pdf a novel mitochondrial protein dip mediates e2f1induced. In the p53dependent pathway, e2f1 activates arf, which in turn stabilizes p53 by alleviating its proteosome degradation through mdm2. Gene expression changes in response to e2f1 activation. We observed that whereas e2f3 caused little apoptosis, an e2f3 chimera containing the e2f1 marked box and flanking region strongly induced apoptosis and both p53 and p73 protein 1corresponding author. In the past, e2f1 was recognized as a key regulator of apoptosis, but the latest evidence reveals that this transcription factor is aberrantly high in latestage cancers and instead of apoptosis promotes tumor invasion and metastasis.
E2f1 controlled genes is required for cell survival. Apoptosis associated with deregulated e2f activity is. Ischemiaapoptosise2f1 transcription factorgene ex pression. Previous work has established a role for p53 in triggering apoptosis in response to. Additionally, e2f1 and e7induced apoptosis are compromised in cells from patients with the. However, the mechanism for crosstalk between the p53 and e2f1 pathways still remains unclear. Furthermore, the mechanism underlying the apoptosis pathway remains to be uncovered. Additional support for this notion comes from the study of rb null mice. Jieduanniwan formula reduces liver apoptosis in a rat. Retinoblastoma 1 protects t cell maturation from premature. A role for the e2f family member e2f1 has been well established in activating the p53 apoptotic signaling pathway upon loss of proliferation control, and recent reports suggest that e2f1 may contribute to apoptosis in response to dna damage 6, 30, 43. E2f1 promotes apoptosis in a p53dependent and p53independent manner.
Because e2f1 regulates the expression of bh3only proteins under dnadamageinduced apoptosis hershko and ginsberg. Thus, tumor formation is enhanced when functional p53 is also absent. Pdf e2f1 death pathways as targets for cancer therapy. E2f1 inhibits cmycdriven apoptosis via pik3caaktmtor. In the p53dependent pathway, e2f1 activates p14 arf, which in turn stabilizes p53 by inhibiting its proteosomal degradation by mouse double minutes 2 mdm2. E2f1 arf p53 pathway induces apoptosis in response to hyperproliferative oncogenic stimulation, e2f1 loss of function suppresses p53dependent apoptosis observed in rbdeficient cells in vivo. E2f1 induces phosphorylation of p53 that is coincident with. In primary human fibroblasts lacking functional atm, the ability of e2f1 to. E2f1 pathways to apoptosis doron ginsberg departmentof molecularcell biology,theweizmanninstitute of science,rehovot76100,israel received 12august2002. Downregulation of e2f1 during er stress is required to.
E2f1 induces phosphorylation of p53 that is coincident. Among them, e2f1 apoptosis proteaseactivating factor 1 apaf1 caspases pathway plays an important role in e2f1 induced apoptosis because e2f1 induced apoptosis is signi. Thus, this study shows that rb and egfrrasraf signaling cooperate to inhibit e2f1 induced apoptosis during normal development. Additionally, e2f1 mediated apoptosis is abolished in the presence of caffeine, an inhibitor of phosphatidylinositol 3kinaserelated kinases that phosphorylate p53. Given the frequent inactivation of p53 in human cancers, the e2f1 induced apoptosis pathway is rapidly gaining attention as a key mechanism to compensate the loss of p53 in human tumors. E2f1induced apoptosis occurs via multiple pathways, some of which induce stabilization and activation of the tumor suppres sor p53. Rb protects from apoptosis 7, whereas e2f1 induces apoptosis 14. And the stage of the affected thymocytes immature or mature also needs to be clarified. Inhibition of e2f1 cdk1 pathway attenuates neuronal apoptosis in vitro and confers neuroprotection after spinal cord injury in vivo. E2f1 accelerates p53 mediated apoptotic activity either by inducing the expression of p19p14arf, an inhibitor of the mdm2 ubiquitin. E2f is involved in radioresistance of carbon ion induced. Novel rhobtb2 antibody is functional in immunofluorescent. In contrast, e2f1 is not required for the induction of apoptosis by glucocorticoids or dna damage. The e2f1 gene well known is its pivotal role in regulating the entry from g1 to s phase, while the salvage antitumoral pathway which implicates it, especially in the absence of p53, is not fully char.
Inhibitors of histone deacetylases target the rbe2f1 pathway. The p53independent apoptosis induced by e2f1 occurs via direct upregulation of p73, apoptosis protease activating. In addition, at least one member of the e2f family, e2f1, can induce apoptosis through a number of p53dependent and independent mechanisms. E2f1 directly activates transcription of p73, lead. Arf negatively regulates e2f1 in a feedback loop mechanism. Changes of e2f1 expressions could partly alter radioresistance in cancer cells.
Comparing effects of cdk inhibition and e2f12 ablation on. Because e2f1 regulates the expression of bh3only proteins under dnadamageinduced apoptosis. Coordination between cell cycle progression and cell fate. E2f1mediated apoptosis as a target of cancer therapy. E2f1 overexpression upregulates rhobtb2 mrna 38 figure 6. E2f1 causes apoptosis via p53dependent and p53independent pathways 4, and this is an effective mechanism for suppressing tumorigenesis. Flavopiridolinduced apoptosis is mediated through up regulation.
Our study provides a scientific rationale for the clinical use of heavy ion as radiotherapy in patients with p53deficient tumors, which are often. Novel rhobtb2 antibody is functional in immunofluorescent microscopy and is specific for rhobtb2 40. Pdf the aryl hydrocarbon receptor binds to e2f1 and inhibits. Distinct roles for e2f proteins in cell growth control and. Given the frequent inactivation of p53 in human cancers, the e2f1 induced apoptosis pathway is rapidly gaining attention as a key mechanism. The best characterized pathway for e2f1 mediated cell. Thus, we asked whether rb and e2f1 also play antagonistic roles in the regulation of autophagy. Oct 02, 2002 e2f1 induced apoptosis is significantly reduced by inhibitors of caspase activity or by gene disruption of apafi, indicating that the e2f1 apaficaspases pathway is an important mediator of e2f1 induced apoptosis.
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