<i>E2f3a</i> and <i>E2f3b</i> Contribute to the Control of Cell Proliferation and Mouse Development

Chong, Jean Leon; Tsai, Shih Yin; Sharma, Nidhi; Opavský, René; Price, Richard L.; Wu, Lizhao; Fernández, Soledad; Leone, Gustavo

doi:10.1128/mcb.01161-08

Cited by 70 publications

(76 citation statements)

References 36 publications

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“…8,10 We were also surprised to observe that E2f3 binds target sites in a highly tissue-specific manner in NPCs compared with MBs. Genetic mouse models have highlighted E2f3 as an important regulator of differentiation in a number of tissues, including brain, skeletal and cardiac muscle, cartilage and adipocytes, 8,24,[50][51][52][53] and our data now suggest that regulation of E2f3-specific target genes is likely to contribute to distinct differentiation programs in these and potentially other cell types. To our knowledge, ours is the first study to demonstrate such a substantial degree of tissue specificity among genomic binding sites for any E2f factor.…”

Section: Discussionsupporting

confidence: 51%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

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Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell typespecific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

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Section: Discussionsupporting

confidence: 51%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

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“…3j). E2F3 has been shown to be sufficient for cell proliferation and normal embryonic and post-natal development [38][39][40] , thus explaining the observed cell cycle progression despite the downregulation of E2F1 by Salmonella.…”

Section: Discussionmentioning

confidence: 99%

Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection

et al. 2014

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Increasing evidence suggests an important role for miRNAs in the molecular interplay\ud between bacterial pathogens and host cells. Here we perform a fluorescence microscopybased\ud screen using a library of miRNA mimics and demonstrate that miRNAs modulate\ud Salmonella infection. Several members of the miR-15 miRNA family were among the\ud 17 miRNAs that more efficiently inhibit Salmonella infection. We discovered that these\ud miRNAs are downregulated during Salmonella infection, through the inhibition of the\ud transcription factor E2F1. Analysis of miR-15 family targets revealed that derepression of\ud cyclin D1 and the consequent promotion of G1/S transition are crucial for Salmonella\ud intracellular proliferation. In addition, Salmonella induces G2/M cell cycle arrest in infected\ud cells, further promoting its replication. Overall, these findings uncover a mechanism whereby\ud Salmonella renders host cells more susceptible to infection by controlling cell cycle\ud progression through the active modulation of host cell miRNAs

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“…E2F3, a member of E2F family of transcription factors, binds specifically to RB1 protein, in a cell cycle-dependent manner, and plays a crucial role in the control of genes regulating S phase entry and DNA synthesis. 39,40 Amplification and overexpression of MDM2 on 12q15 were detected in 1 high-grade Ta case that presented with recurrences (Table 2). MDM2 overexpression has been shown to correlate with increasing stages and grades in urinary bladder cancer 41 and MDM2 amplification and TP53 mutation to be mutually exclusive 42 because MDM2 is a specific antagonist of TP53 activity.…”

Section: Discussionmentioning

confidence: 99%

Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma

Nord

Segersten

Sandgren

et al. 2009

Intl Journal of Cancer

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Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating tumors (stage T21). The risk of progression and death for the most frequent diagnosed type, Ta, is low, but the high incidence of recurrences has a significant effect on the patients' quality of life and poses substantial costs for health care systems. Consequently, the purpose of this study was to search for predictive factors of recurrence on the basis of genetic profiling. A clinically well characterized cohort of Ta bladder carcinomas, selected by the presence or absence of recurrences, was evaluated by an integrated analysis of DNA copy number changes and gene expression (clone-based 32K, respectively, U133Plus2.0 arrays). Only a few chromosomal aberrations have previously been defined in superficial bladder cancer. Surprisingly, the profiling of Ta tumors with a high-resolution array showed that DNA copy alterations are relatively common in this tumor type. Furthermore, we observed an overrepresentation of focal amplifications within high-grade and recurrent cases. Known (FGFR3, CCND1, MYC, MDM2) and novel candidate genes were identified within the loci. For example, MYBL2, a nuclear transcription factor involved in cell-cycle progression; YWHAB, an antiapoptotic protein; and SDC4, an important component of focal adhesions represent interesting candidates detected within two amplicons on chromosome 20, for which DNA amplification correlated with transcript up-regulation. The observed overrepresentation of amplicons within high-grade and recurrent cases may be clinically useful for the identification of patients who will benefit from a more aggressive therapy.Urinary bladder cancer is a common malignant disease that ranks fourth among all cancers in Europe with 91,000 new cases and 37,000 deaths annually. 1 The prevalence is 3 to 8 times higher than the incidence, making bladder cancer one of the most prevalent neoplasms, and hence, a major burden for all health care systems. The biology of this disease is heterogeneous with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating high-grade tumors (stage T2þ). The histologic grade usually parallels the stage, and thus, low-grade is common in lower, whereas high-grade predominates in higher stages. The most frequent form of all newly diagnosed cancers is of the stage Ta category, usually of low grade, which constitute more than half of all newly diagnosed cases. These tumors are considered to evolve from urothelial hyperplasia and are often multifocal. After initial transurethral resection (TUR), approximately 70% recur in the bladder, which makes this tumor type responsible for the high prevalence rate. The risk of progression and death is small, but the frequency of recurrences has a significant effect on the patients' quality of life and poses a substantial cost for the health care systems. Consequently, an attempt to prevent recurrences is frequently made by intravesical instillations either by...

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E2f3a and E2f3b Contribute to the Control of Cell Proliferation and Mouse Development

Cited by 70 publications

References 36 publications

Tissue-specific targeting of cell fate regulatory genes by E2f factors

Tissue-specific targeting of cell fate regulatory genes by E2f factors

Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection

Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma

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