Synergistic Function of E2F7 and E2F8 Is Essential for Cell Survival and Embryonic Development

Li, Jing; Ran, Cong; Li, Edward; Gordon, Faye; Comstock, Grant; Siddiqui, Hasan; Cleghorn, Whitney M.; Chen, Hui Zi; Kornacker, Karl; Liu, Chang Gong; Pandit, Shusil K.; Khanizadeh, Mehrbod; Weinstein, Michael; Leone, Gustavo; Bruin, Alain de

doi:10.1016/j.devcel.2007.10.017

Cited by 194 publications

(293 citation statements)

References 45 publications

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“…In particular, little is known about the physiological role of the recently identified E2F7 factor. 36,37 Taken together, the current study provides the first direct evidence that hTERT expression is induced in proliferating hepatocytes in vivo and in vitro. hTERT could be one of the essential factors ensuring the regenerative capacity of human liver.…”

Section: Discussionsupporting

confidence: 55%

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

et al. 2011

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Section: Discussionsupporting

confidence: 55%

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

et al. 2011

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“…They are considered to function as transcriptional repressors of certain E2F-responsive genes, by mechanisms that differ from the conventional mode of E2F-mediated regulation. 8,9 A considerable amount of evidence has accumulated indicating that this division of E2F members into activators and repressors may be too simplistic. Indeed, microarray analyses have shown that ectopic expression of E2F1-3 not only leads to transcriptional activation, but also to the transcriptional repression of a large number of genes, 10,11 although, of course, many of these effects may be indirect.…”

Section: Introductionmentioning

confidence: 99%

E2F2 represses cell cycle regulators to maintain quiescence

Infante

Laresgoiti²,

Fernández-Rueda³

et al. 2008

Cell Cycle

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E2F transcription factors control diverse biological processes through regulation of target gene expression. However, the mechanism by which this regulation is established, and the relative contribution of each E2F member are still poorly defined. We have investigated the role of E2F2 in regulating cellular proliferation. We show that E2F2 is required for the normal G 0 /G 1 phase because targeted disruption of the E2F2 gene causes T cells to enter S phase early and to undergo accelerated cell division. A large set of E2F target genes involved in DNA replication and cell cycle progression (such as Mcm's, cyclins and Cdc2a) that are silent in G 0 and typically transcribed late in G 1 phase are already actively expressed in quiescent T cells and MEFs lacking E2F2. The classic E2F activators, E2F1 and E2F3, are largely dispensable for this process because compound loss of E2F1 -/-and E2F2 -/-produces a comparably shortened G 0 /G 1 phase, with early S phase entry. Likewise, shRNA knockdown of E2F3 does not alter significantly the E2F2 -/-phenotype. Chromatin immunoprecipitation analysis indicates that in wild-type cells the promoters of the aberrantly early-transcribed genes are occupied by E2F2 in G 0 , suggesting a direct role for E2F2 in transcriptional repression. We conclude that E2F2 functions to transcriptionally repress cell cycle genes to establish the G 0 state.

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“…1f and data not shown). Given the observed functional redundancy among E2Fs during embryonic development 8,11,14 , we reasoned that loss of additional E2F activators might accentuate the rather mild agedependent phenotype in E2f3a −/− mice. Both E2f1 −/− and E2f2 −/− mice were previously shown to have a relatively normal life span, but with age these mice developed hematopoietic related complications [15][16][17][18][19] .…”

mentioning

confidence: 99%

“…These results suggest that E2f3a and E2f3b have redundant functions during embryonic development. Because of the functional plasticity that exists among E2F family members 8,[11][12][13] , we examined the consequences of inactivating E2f3a or E2f3b in combination with the other two known E2F activators, E2f1 and E2f2. From the intercrosses described in Fig.…”

mentioning

confidence: 99%

Mouse development with a single E2F activator

Tsai

Opavský

Sharma

et al. 2008

Nature

Self Cite

107

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The E2F family is conserved from C. elegans to mammals with some family members having transcription activation functions and others having repressor functions 1, 2 . Whereas C. elegans 3 and Drosophila melanogaster 4, 5 have a single E2F activator and repressor proteins, mammals evolved to have at least three activator and five repressor proteins 1,2,6 . Why such genetic complexity evolved in mammals is not known. To begin to evaluate this genetic complexity, we targeted the inactivation of the entire subset of activators, E2f1, E2f2, E2f3a and E2f3b, singly or in combination in mice. We demonstrate that E2f3a is sufficient to support mouse embryonic and postnatal development. Remarkably, expression of E2f3b or E2f1 from the E2f3a locus (E2f3a 3bki ; E2f3a 1ki ) suppressed all the postnatal phenotypes associated with the inactivation of E2f3a. We conclude that there is significant functional redundancy among activators and that the specific requirement for E2f3a during postnatal development is dictated by regulatory sequences governing its selective spatiotemporal expression and not by its intrinsic protein functions. These findings provide a molecular basis for the observed specificity among E2F activators during development. KeywordsE2F3a; E2F3b; Rb; development; proliferation; transcription and apoptosis Since the identification of the founding E2F family member, E2f1 7 , two distinct genes in lower eukaryotes and eight genes in higher eukaryotes have been identified to encode the signature DNA binding domain that endow these transcription factors with E2F 1,2,6 . Among the mammalian E2F activator subset, the E2f3 gene has emerged as the critical family member involved in the control of cell proliferation and development 8,9 . The E2f3 locus was originally thought to encode a single DNA binding activity, but was later shown to drive the expression of two related isoforms, E2f3a and E2f3b, from two distinct promoters 10 . Given the critical link between the E2f3 locus and the control of cell proliferation, we used homologous recombination to individually disrupt its two isoforms in mice and rigorously evaluate how their functions are integrated with that of other E2F activators. The inactivation of E2f3a or E2f3b was achieved by targeting exon 1a or 1b sequences, respectively, using LoxP-cre technology (Fig. 1a). Mice deleted for either exon 1a or exon 1b were identified by Southern blot and genomic PCR analysis (Fig. 1b). Specific ablation of E2f3a or E2f3b was confirmed by Western blot assays using total E2F3-specific antibodies (Fig. 1c).It was previously shown that inactivation of both E2f3a and E2f3b (E2f3 −/− ) in mice with a mixed strain background yielded offspring that developed rather normally 8, 9 , but we show here that breeding these mice into a pure strain background (∼98% pure) resulted in embryonic lethality ( Fig. 1e and Supplementary Fig. 1). Intercrossing E2f3 +/− mice of different pure backgrounds restored viability of E2f3 −/− mice, albeit with some observed strain-specific biase...

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Synergistic Function of E2F7 and E2F8 Is Essential for Cell Survival and Embryonic Development

Cited by 194 publications

References 45 publications

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

E2F2 represses cell cycle regulators to maintain quiescence

Mouse development with a single E2F activator

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