Accumulation of E2F-4·DP-1 DNA Binding Complexes Correlates with Induction of dhfr Gene Expression during the G1 to S Phase Transition

Wells, Julie; Illenye, Sharon; Magae, Junji; Wu, Chin‐Lee; Heintz, Nicholas H.

doi:10.1074/jbc.272.7.4483

Cited by 38 publications

(43 citation statements)

References 61 publications

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“…This view is supported by the observation that mice bearing homozygous deletions of the E2F-1 gene do not have defects in cell proliferation, but rather show an increased tendency to develop tumors (Field et al, 1996;Yamasaki et al, 1996;Zwicker et al, 1996). Nevertheless, once its association with pRb family proteins is disrupted, E2F also seems to be a positive regulator of certain genes, such as dhfr (Wells et al, 1997) and b-myb (Lam et al, 1995).…”

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confidence: 92%

pRb and p107 regulate E2F activity during lens fiber cell differentiation

et al. 1998

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During growth arrest and di erentiation, activity of the E2F family of transcription factors is inhibited by interactions with pRb and the related proteins, p107 and p130. To determine which members of the E2F and pRb families may contribute to growth arrest as lens epithelial cells di erentiate into ®ber cells, we examined the expression of individual E2F species and characterized the E2F protein complexes formed in rat lens epithelia and ®bers. RT/PCR detected all ®ve known members of the E2F family in lens epithelial cells, but only E2F-1, E2F-3, and E2F-5 in ®ber cells. Proteins extracted from lens epithelia of newborn rats formed at least two speci®c complexes with an E2F consensus oligonucleotide. Proteins from lens ®ber cells formed three speci®c complexes, one of which comigrated with an epithelial cell complex. Incubation of epithelial and ®ber cell extracts with an antibody speci®c for p107 demonstrated that two ®ber cell complexes and one epithelial cell complex contained p107. Although the remaining ®ber cell complex did not react with antibodies to pRb or p130 in this assay, a strong reaction with pRb antibody was observed when the electromobility shifted complexes were subsequently immunoblotted (shift/Western assay). Immunocytochemistry con®rmed that pRb protein is present in the nuclei of both epithelial cells and ®ber cells. Immunoblotting of whole cell extracts with pRb antibody showed multiple, phosphorylated forms of pRb in the epithelial cells, but predominantly hypophosphorylated pRb in the ®ber cells. None of the complexes formed with E2F were recognized exclusively by the p130 antibody, although the previously identi®ed p107 complexes reacted weakly. The absence of p130/E2F complexes was correlated with the presence of multiple ubiquitinated forms of p130, especially in the ®ber cells. Thus, although p130/E2F complexes are implicated in the terminal di erentiation of many cell types, in di erentiating lens ®ber cells pRb and p107 seem to be the primary regulators of E2F activity.

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confidence: 92%

pRb and p107 regulate E2F activity during lens fiber cell differentiation

et al. 1998

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“…Functional E2F binding sites are present in the promoters of nearly all genes that control cell cycle progression (3,24,27,32,41). Several lines of evidence suggest that the E2F family of transcription factors may stimulate productive BoHV-1 infection and reactivation from latency.…”

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Productive Infection and bICP0 Early Promoter Activity of Bovine Herpesvirus 1 Are Stimulated by E2F1

Workman

Jones

2010

J Virol

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Bovine herpesvirus 1 (BoHV-1) is an important viral pathogen of cattle. Like other members of the subfamily Alphaherpesvirinae, BoHV-1 establishes latency in sensory neurons and has the potential to reactivate from latency. Dexamethasone (DEX) treatment of latently infected calves or rabbits consistently leads to reactivation from latency. The BoHV-1 transcript encoding the infected cell protein 0 (bICP0) is consistently detected during reactivation from latency, in part because the bICP0 early promoter is activated by DEX. During DEX-induced reactivation from latency, cyclin expression is stimulated in infected sensory neurons. Cyclindependent kinase activity phosphorylates Rb (retinoblastoma tumor suppressor gene product) family proteins and consequently releases the E2F family of transcription factors, suggesting that E2F family members stimulate productive infection and/or reactivation from latency. In this study, we provide evidence that repression of E2F1 by a specific small interfering RNA (siRNA) reduced productive infection approximately 5-fold. E2F1 or E2F2 stimulated bICP0 early promoter activity at least 100-fold in transient transfection assays. Two E2F-responsive regions (ERR) were identified within the early promoter, with one adjacent to the TATA box (ERR1) and one approximately 600 bp upstream from the TATA box (ERR2). Mobility shift assays suggested that E2F interacts with ERR1 and ERR2. E2F1 protein levels were increased at late times after infection, which correlated with enhanced binding to a consensus E2F binding site, ERR1, or ERR2. Collectively, these studies suggest that E2F1 stimulates productive infection and bICP0 early promoter activity, in part because E2F family members interact with ERR1 and ERR2.Bovine herpesvirus 1 (BoHV-1) is a significant viral pathogen of cattle that can cause conjunctivitis, rhinotracheitis, pneumonia, genital disorders, or abortions. BoHV-1 also initiates shipping fever, a potentially fatal polymicrobial disease (37). Like other members of the Alphaherpesvirinae subfamily, BoHV-1 establishes lifelong latency in trigeminal ganglionic neurons following acute replication in mucosal epithelium. Reactivation from latency occurs periodically, resulting in virus shedding and spread to susceptible cattle. Reactivation from latency can occur after stress or corticosteroid treatment, which mimics stress (30, 34). Dexamethasone (DEX), a synthetic corticosteroid, reproducibly induces expression of BoHV-1 lytic cycle genes and reactivation from latency in calves or rabbits (15,(17)(18)(19)(20)30).During productive infection of cultured cells, viral gene expression is temporally regulated in three distinct phases: the immediate-early (IE), early (E), and late (L) phases (reviewed in references 17 and 18). IE gene expression is stimulated by a virion component, bTIF, which interacts with a cellular transcription factor (Oct-1) to transactivate IE gene expression (22,23). Two IE transcription units exist, namely, IE transcription unit 1 (IEtu1) and IEtu2 (44-46). IEtu1 enc...

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“…This site is present in the promoters of many growthresponsive and growth-promoting genes, including c-myc, DNA polymerase-␣, cyclin-dependent kinases, and cyclin D1 (Herber et al, 1994;Pearson et al, 1991;Sardet et al, 1995;Vairo et al, 1995). E2F-4 regulates these genes, in part, through their interaction with members of the pocket proteins (pRb, p130, and p107) (Li et al, 1997;Liu et al, 1998;Sardet et al, 1995;Wells et al, 1997). An important role for E2Fs in the development of cancer is suggested by the finding that, in most human neoplasia, genetic or epigenetic alterations occur that ultimately result in the deregulation of E2F-dependent transcription.…”

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Effect of Naturally Occurring E2F-4 Alterations on Transcriptional Activation and Proliferation in Transfected Cells

Takashima

Matsumoto

Matsubara

et al. 2001

Laboratory Investigation

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SUMMARY:E2F is a family of transcription factors implicated in the regulation of gene expression required for progression through the G 1 -S transition. We have previously detected tumor-specific mutations at a trinucleotide repeat coding sequence of E2F-4 gene in a subset of human sporadic colorectal cancers. The purpose of this study was to investigate the potential functional consequences of these E2F-4 mutations. We transfected NIH3T3 fibroblasts with expression constructs containing wild-type as well as mutant E2F-4 cDNA, and the effect of the E2F-4 mutations on proliferation was examined. Alteration in transactivation of the E2F consensus promoter sequence was also examined by transient cotransfection of a E2F-4 with a DP-2 construct into cultured human cells. Transfected cell clones overexpressing mutant E2F-4 grew more rapidly and showed higher proliferative activity by increased immunohistochemical staining for proliferating cell nuclear antigen (PCNA). All three mutant forms of E2F-4 showed elevated transactivation of the E2F consensus promoter sequence. Thus, expression of mutant E2F-4s confers a growth advantage in vivo, and this effect may be related to the acquisition of a neoplastic phenotype. (Lab Invest 2001, 81:1565-1573.T he E2F family of transcription factors (E2F-1, -2, -3, -4, -5, and -6) has been implicated in the regulation of cell cycle, particularly at the level of G 1 -S progression, as well as in the regulation of apoptotic

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Accumulation of E2F-4·DP-1 DNA Binding Complexes Correlates with Induction of dhfr Gene Expression during the G1 to S Phase Transition

Cited by 38 publications

References 61 publications

pRb and p107 regulate E2F activity during lens fiber cell differentiation

pRb and p107 regulate E2F activity during lens fiber cell differentiation

Productive Infection and bICP0 Early Promoter Activity of Bovine Herpesvirus 1 Are Stimulated by E2F1

Effect of Naturally Occurring E2F-4 Alterations on Transcriptional Activation and Proliferation in Transfected Cells

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