E2F2 and CREB cooperatively regulate transcriptional activity of cell cycle genes

Laresgoiti, Usua; Apraiz, Aintzane; Olea, Miguel; Mitxelena, Jone; Osinalde, Nerea; Rodriguez, José Antonio; Fullaondo, Asier; Zubiaga, Ana M.

doi:10.1093/nar/gkt821

Cited by 47 publications

(38 citation statements)

References 50 publications

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“…This could be because the proteins left over after the knockdown are sufficient to repress the gene expression and/or knockdown of one protein in the repressor complex is not enough to overturn the repression. Nevertheless, similar results were observed in other siRNA knockdown studies (39, 40). The fold repression (39) decreased at least by 33% in each siRNA knockdown group compared with control siRNA (data not shown).…”

Section: Resultssupporting

confidence: 91%

Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG‐rich motifs

Han

Kwong

et al. 2016

FASEB j.

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Trocarin D (TroD), a venom prothrombin activator from Tropidechis carinatus, shares similar structure and function with blood coagulation factor Xa [Tropidechis carinatus FX (TrFX) a]. Their distinct physiologic roles are due to their distinct expression patterns. The genes of TroD and TrFX are highly similar, except for promoter and intron 1, indicating that TroD has probably evolved by duplication of FX, the plasma counterpart. The promoter insertion in TroD accounts for the elevated but not venom gland-specific expression. Here we examined the roles of 3 insertions and 2 deletions in intron 1 of TroD in the regulation of expression using luciferase as a reporter. By systematic deletions, we showed that a 209 bp region within the second insertion silences expression in mammalian and unmilked venom gland cells. Through bioinformatics analysis, we identified 5 AG-rich motifs in this region. All except the 5th motif are important for silencing function. YY1, Sp3 and HMGB2 were identified to bind these AG-rich motifs and silence gene expression in mammalian cells. Similar AG-rich motif clusters are also found in other toxin genes but not in their physiologic counterparts. Thus, AG-rich motifs contribute to regulation of expression of TroD, and probably other toxin genes.-Han, S. X., Kwong, S., Ge, R., Kolatkar, P. R., Woods, A. E., Blanchet, G., Kini, R. M. Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG-rich motifs.

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Section: Resultssupporting

confidence: 91%

Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG‐rich motifs

Han

Kwong

et al. 2016

FASEB j.

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“…Third, according to Laresgoiti and co-workers CREB1 reinforces the repressive function of E2F2. 21 This reinforcement could be the final trigger for switching the interaction mode between GLI1 and GLI3. Whether such a cooperative repressive mechanism is active in hepatocytes and could actually be both, target and regulator of GLI function remains to be investigated.…”

Section: Fuzzy Modeling Of the Gli Factor Networkmentioning

confidence: 99%

Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes

et al. 2015

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The GLI transcription factors, GLI1, GLI2, and GLI3, transduce Hedgehog and non-hedgehog signals and are involved in regulating development and tumorgenesis. Surprisingly, they were recently found to modulate important functions of mature liver. However, less is known about their mutual interactions and possible target genes in mature hepatocytes. To get a deeper insight into these interactions cultured mouse hepatocytes were transfected with siRNAs against each GLI factor. RNA was extracted at different times and the expression levels of the genes of interest were determined by quantitative real-time PCR. The time-dependent data were analysed by a fuzzy logic-based modelling approach. The results indicated that the GLI factors constitute an interconnected network. GLI2 inhibited GLI1 expression and was coupled with GLI3 by a positive feedback loop. The regulatory activity between GLI1 and GLI3 was more complex switching between a positive and a negative feedback loop depending on whether the level of GLI2 is low or high, respectively. Generally, this network structure enables a dynamic behaviour. When GLI2 is low, it may keep GLI1 and GLI3 activity balanced favouring the appropriate modulation of transcription factors like the Ppars and Srebp1. When GLI2 is high, it may prevent an uncontrolled amplification that may lead to cancer. In conclusion, the three GLI factors in mature hepatocytes form an interactive transcriptional network that is involved in the control of target genes associated with metabolic zonation as well as with lipid and drug metabolism. Its structure in mature cells seems different from embryonic cells.

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“…To identify genes and pathways directly regulated by E2F2, we utilized publicly available E2F2 ChIP-Chip data (Figure 1D) (33). This revealed numerous genes bound by E2F2 across the genome.…”

Section: Resultsmentioning

confidence: 99%

“…For the E2F2 overexpression data, Affymetrix cDNA microarray profiled gene expression data was downloaded from previously published data (40). For E2F2 binding analysis we utilized ChIP-Chip for data for E2F2 T lymphocytes isolated from 4-week-old C57B16:129SV mice (33). For the E2F2 knockout data in the MMTV-Neu background we utilized the dataset GSE42533.…”

Section: Methodsmentioning

confidence: 99%

Low E2F2 activity is associated with high genomic instability and PARPi resistance

Rennhack

Andrechek

2019

Preprint

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34The E2F family, classically known for a central role in cell cycle, has a number of emerging roles 35 in cancer including angiogenesis, metabolic reprogramming, metastasis and DNA repair. E2F1 36 specifically has been shown to be a critical mediator of DNA repair; however, little is known about 37 DNA repair and other E2F family members. Here we present an integrative bioinformatic and 38 high throughput drug screening study to define the role of E2F2 in maintaining genomic integrity 39 in breast cancer. We utilized in vitro E2F2 ChIP-chip and over expression data to identify 40 transcriptional targets of E2F2. This data was integrated with gene expression from E2F2 41 knockout tumors in an MMTV-Neu background. Finally, this data was compared to human 42 datasets to identify conserved roles of E2F2 in human breast cancer through the TCGA breast 43 cancer, Cancer Cell Line Encyclopedia, and CancerRx datasets. Here we have computationally 44 predicted that E2F2 transcriptionally regulates key mediators of DNA repair. Our gene expression 45 data supports this hypothesis and low E2F2 activity is associated with a highly unstable tumor. In 46 human breast cancer E2F2, status was also correlated with a patient's response to PARP inhibition 47 therapy. Taken together this manuscript defines a novel role of E2F2 in cancer progression beyond 48 cell cycle and could be therapeutically relevant. 49 50 Author Summary 51 The E2F family of proteins have been known to regulate cell cycle and have recently been shown 52to have a number of roles in tumor progression. Here we use a combination of computational 53 techniques and high-throughput drug screening data to establish a novel role of E2F2 in 54 maintaining genomic integrity. We have shown that a number of direct and indirect target genes 55 of E2F2 are involved in multiple classical DNA repair pathways. Importantly, this was shown to 56 3 be unique to E2F2 and not present with other activator E2Fs like E2F1. We have also shown that 57 E2F2 activity is positively correlated with PARP inhibitor sensitivity regardless of BRCA1/2 58 status. This is important due to the recent approval of PARP inhibitor therapy in the clinic. Based 59 on our work E2F2 activity could serve as a novel biomarker of response and may identify a new 60 cohort of patients which could benefit from PARPi therapy. 61 62 Keywords 63 Genomic stability, breast cancer, E2F transcription factors, mouse model 64 130 ontology groups were overrepresented, including DNA repair and double-stranded break repair 131 ( Figure 1E). Given the similar pathways it was surprising that when we compared predicted E2F2 132 targets obtained through ChIP-Chip and gene expression analysis that we identified little overlap 133 in the gene lists ( Figure 1F). This may indicate that the pathways are regulated by both direct and 134 indirect / downstream targets of E2F2. To determine if there was bias towards one particular repair 135 pathway, we identified overlap between E2F2 regulated genes (gene expression and ChIP-chip) 1...

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E2F2 and CREB cooperatively regulate transcriptional activity of cell cycle genes

Cited by 47 publications

References 50 publications

Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG‐rich motifs

Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG‐rich motifs

Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes

Low E2F2 activity is associated with high genomic instability and PARPi resistance

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