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Minhee Kim, Jack P Tang, Nam-Sung Moon
Across metazoans, cell cycle progression is regulated by E2F family transcription factors that can function as either transcriptional activators or repressors. For decades, the Drosophila E2F family has been viewed as a streamlined RB/E2F network, consisting of one activator (dE2F1) and one repressor (dE2F2). Here, we report that an uncharacterized isoform of dE2F1, hereon called dE2F1b, plays an important function during development and is functionally distinct from the widely-studied dE2F1 isoform, dE2F1a...
February 2018: PLoS Genetics
Mary-Rose Bradley-Gill, Minhee Kim, Daniel Feingold, Christine Yergeau, Josée Houde, Nam-Sung Moon
The E2F family of transcription factors are evolutionarily conserved regulators of the cell cycle that can be divided into two groups based on their ability to either activate or repress transcription. In Drosophila, there is only one "activator" E2F, dE2F1, which provides all of the pro-proliferative activity of E2F during development. Interestingly, the de2f1 gene can be transcribed from multiple promoters resulting in six alternate transcripts. In this study, we sought to investigate the biological significance of the alternate transcriptional start sites...
March 15, 2016: Developmental Biology
Yiliang Wei, Shamba S Mondal, Rima Mouawad, Bartek Wilczyński, R William Henry, David N Arnosti
RBf2 is a recently evolved retinoblastoma family member in Drosophila that differs from RBf1, especially in the C-terminus. To investigate whether the unique features of RBf2 contribute to diverse roles in gene regulation, we performed chromatin immunoprecipitation sequencing for both RBf2 and RBf1 in embryos. A previous model for RB-E2F interactions suggested that RBf1 binds dE2F1 or dE2F2, whereas RBf2 is restricted to binding to dE2F2; however, we found that RBf2 targets approximately twice as many genes as RBf1...
July 2015: G3: Genes—Genomes—Genetics
A Clavier, A Baillet, A Rincheval-Arnold, A Coléno-Costes, C Lasbleiz, B Mignotte, I Guénal
The retinoblastoma gene, rb, ensures at least its tumor suppressor function by inhibiting cell proliferation. Its role in apoptosis is more complex and less described than its role in cell cycle regulation. Rbf1, the Drosophila homolog of Rb, has been found to be pro-apoptotic in proliferative tissue. However, the way it induces apoptosis at the molecular level is still unknown. To decipher this mechanism, we induced rbf1 expression in wing proliferative tissue. We found that Rbf1-induced apoptosis depends on dE2F2/dDP heterodimer, whereas dE2F1 transcriptional activity is not required...
2014: Cell Death & Disease
Mary Truscott, Abul B M M K Islam, James Lightfoot, Núria López-Bigas, Maxim V Frolov
The importance of microRNAs in the regulation of various aspects of biology and disease is well recognized. However, what remains largely unappreciated is that a significant number of miRNAs are embedded within and are often co-expressed with protein-coding host genes. Such a configuration raises the possibility of a functional interaction between a miRNA and the gene it resides in. This is exemplified by the Drosophila melanogaster dE2f1 gene that harbors two miRNAs, mir-11 and mir-998, within its last intron...
July 2014: PLoS Genetics
Pradeep Kumar Bhaskar, Satya Surabhi, Bipin Kumar Tripathi, Ashim Mukherjee, Mousumi Mutsuddi
Drosophila lin52 (dlin52) is a member of Myb transcription regulator complex and it shows a dynamic pattern of expression in all Drosophila tissues. Myb complex functions to activate or repress transcription in a site-specific manner; however, the detailed mechanism is yet to be clearly understood. Members of the Drosophila melanogaster Myb-MuvB/dREAM complex have been known to regulate expression of a wide range of genes including those involved in regulating apoptosis. E2F and its corepressor RBF also belong to this complex and together they regulate expression of genes involved in cell cycle progression, apoptosis, differentiation, and development...
September 2014: Biochimica et Biophysica Acta
Gabriel M Gordon, Tianyi Zhang, Jiong Zhao, Wei Du
Synthetic lethality is a potential strategy for cancer treatment by specifically promoting the death of cancer cells with particular defects such as the loss of the RB (RB1) tumor suppressor. We previously showed that inactivation of both RB and TSC2 induces synergistic apoptosis during the development of Drosophila melanogaster and in cancer cells. However, the in vivo mechanism of this synthetic-lethal interaction is not clear. Here, we show that synergistic cell death in tissues that have lost the RB and TSC orthologs rbf and dtsc1/gig, respectively, or overexpress Rheb and dE2F1, are correlated with synergistic defects in G1-S control, which causes cells to accumulate DNA damage...
May 1, 2013: Journal of Cell Science
Jun-Yuan Ji, Wayne O Miles, Michael Korenjak, Yani Zheng, Nicholas J Dyson
The E2F transcription factors are important regulators of the cell cycle whose function is commonly misregulated in cancer. To identify novel regulators of E2F1 activity in vivo, we used Drosophila to conduct genetic screens. For this, we generated transgenic lines that allow the tissue-specific depletion of dE2F1 by RNAi. Expression of these transgenes using Gal4 drivers in the eyes and wings generated reliable and modifiable phenotypes. We then conducted genetic screens testing the capacity of Exelixis deficiencies to modify these E2F1-RNAi phenotypes...
December 2012: G3: Genes—Genomes—Genetics
Battuya Bayarmagnai, Brandon N Nicolay, Abul B M M K Islam, Nuria Lopez-Bigas, Maxim V Frolov
The Hippo signaling pathway regulates organ size by controlling the activity of the transcriptional co-activator Yorkie (Yki). Yki is recruited to its target genes by DNA-binding proteins such as Scalloped (Sd). In addition, transcription factor dE2f1, of the Retinoblastoma (Rb) pathway, cooperates with Yki/Sd to synergistically activate a set of common cell cycle target genes. However, little is known about other factors that ensure the proper transcriptional output of Hippo signaling. In this report we identified the chromatin protein GAGA factor (GAF), which is encoded by the Trithorax-like (Trl) gene, as a novel and critical partner in transcriptional regulation by Yki/Sd and dE2f1...
November 15, 2012: Cell Cycle
Anabel Herr, Michelle Longworth, Jun-Yuan Ji, Michael Korenjak, David M Macalpine, Nicholas J Dyson
BACKGROUND: Microarray studies have shown that the E2F transcription factor influences the expression of many genes but it is unclear how many of these targets are important for E2F-mediated control of cell proliferation. RESULTS: We assembled a collection of mutant alleles of 44 dE2F1-dependent genes and tested whether these could modify visible phenotypes caused by the tissue-specific depletion of dE2F1. More than half of the mutant alleles dominantly enhanced de2f1-dsRNA phenotypes suggesting that the in vivo functions of dE2F1 can be limited by the reduction in the level of expression of many different targets...
November 2012: Developmental Dynamics: An Official Publication of the American Association of Anatomists
Michael Korenjak, Endre Anderssen, Sridhar Ramaswamy, Johnathan R Whetstine, Nicholas J Dyson
The retinoblastoma (RB) family of proteins regulate transcription. These proteins lack intrinsic DNA-binding activity but are recruited to specific genomic locations through interactions with sequence-specific DNA-binding factors. The best-known target of RB protein (pRB) is the E2F transcription factor; however, many other chromatin-associated proteins have been described that may allow RB family members to act at additional sites. To gain a perspective on the scale of E2F-dependent and E2F-independent functions, we generated genome-wide binding profiles of RBF1 and dE2F proteins in Drosophila larvae...
November 2012: Molecular and Cellular Biology
Nitin Raj, Liang Zhang, Yiliang Wei, David N Arnosti, R William Henry
The E2F family of transcription factors contributes to oncogenesis through activation of multiple genes involved in cellular proliferation, a process that is opposed by the Retinoblastoma tumor suppressor protein (RB). RB also increases E2F1 stability by inhibiting its proteasome-mediated degradation, but the consequences of this post-translational regulation of E2F1 remain unknown. To better understand the mechanism of E2F stabilization and its physiological relevance, we examined the streamlined Rbf1-dE2F1 network in Drosophila...
October 15, 2012: Cell Cycle
Wayne O Miles, Katrin Tschöp, Anabel Herr, Jun-Yuan Ji, Nicholas J Dyson
E2F transcription factors are important regulators of cell proliferation and are frequently dysregulated in human malignancies. To identify novel regulators of E2F function, we used Drosophila as a model system to screen for mutations that modify phenotypes caused by reduced levels of dE2F1. This screen identified components of the Pumilio translational repressor complex (Pumilio, Nanos, and Brain tumor) as suppressors of dE2F1-RNAi phenotypes. Subsequent experiments provided evidence that Pumilio complexes repress dE2F1 levels and that this mechanism of post-transcriptional regulation is conserved in human cells...
February 15, 2012: Genes & Development
Pradeep Kumar Bhaskar, Ashim Mukherjee, Mousumi Mutsuddi
The DREAM (DP, RB, E2F and MuvB) complex is required in humans to arrest the expression of cell cycle genes during quiescence. One of its members LIN52 has been isolated from the repressor complex but little is known about its molecular function. It has been reported recently that the serine residue 28 of LIN52 is phosphorylated by DYRK1A, and point mutation of this residue or down regulation of DYRK1A (which phosphorylates LIN52) leads to disruption of DREAM complex assembly, which is needed for G(0) arrest...
January 2012: Gene Expression Patterns: GEP
Madina J Sukhanova, Latishya J Steele, Tianyi Zhang, Gabriel M Gordon, Wei Du
The retinoblastoma gene Rb is the prototype tumor suppressor and is conserved in Drosophila. We use the developing fly retina as a model system to investigate the role of Drosophila Rb (rbf) during differentiation. This report shows that mutation of rbf and rhinoceros (rno), which encodes a PHD domain protein, leads to a synergistic delay in photoreceptor cell differentiation in the developing eye disc. We show that this differentiation delay phenotype is caused by decreased levels of different components of the Epidermal Growth Factor Receptor (EGFR) signaling pathway in the absence of rbf and rno...
November 15, 2011: Developmental Biology
Mary Truscott, Abul B M M K Islam, Núria López-Bigas, Maxim V Frolov
The E2F family of transcription factors regulates the expression of both genes associated with cell proliferation and genes that regulate cell death. The net outcome is dependent on cellular context and tissue environment. The mir-11 gene is located in the last intron of the Drosophila E2F1 homolog gene dE2f1, and its expression parallels that of dE2f1. Here, we investigated the role of miR-11 and found that miR-11 specifically modulated the proapoptotic function of its host gene, dE2f1. A mir-11 mutant was highly sensitive to dE2F1-dependent, DNA damage-induced apoptosis...
September 1, 2011: Genes & Development
Brandon N Nicolay, Battuya Bayarmagnai, Abul B M M K Islam, Nuria Lopez-Bigas, Maxim V Frolov
The Hippo signaling pathway regulates organ size homeostasis, while its inactivation leads to severe hyperplasia in flies and mammals. The transcriptional coactivator Yorkie (Yki) mediates transcriptional output of the Hippo signaling. Yki lacks a DNA-binding domain and is recruited to its target promoters as a complex with DNA-binding proteins such as Scalloped (Sd). In spite of recent progress, an open question in the field is the mechanism through which the Yki/Sd transcriptional signature is defined. Here, we report that Yki/Sd synergizes with and requires the transcription factor dE2F1 to induce a specific transcriptional program necessary to bypass the cell cycle exit...
February 15, 2011: Genes & Development
Ting-Chiu Hsieh, Brandon N Nicolay, Maxim V Frolov, Nam-Sung Moon
Previous studies in Drosophila melanogaster have demonstrated that many tumor suppressor pathways impinge on Rb/E2F to regulate proliferation and survival. Here, we report that Tuberous Sclerosis Complex 1 (TSC1), a well-established tumor suppressor that regulates cell size, is an important regulator of dE2F1 during development. In eye imaginal discs, the loss of tsc1 cooperates with rbf1 mutations to promote ectopic S-phase and cell death. This cooperative effect between tsc1 and rbf1 mutations can be explained, at least in part, by the observation that TSC1 post-transcriptionally regulates dE2F1 expression...
August 19, 2010: PLoS Genetics
Anita Wichmann, Lyle Uyetake, Tin Tin Su
The ability of ionizing radiation (IR) to induce apoptosis independent of p53 is crucial for successful therapy of cancers bearing p53 mutations. p53-independent apoptosis, however, remains poorly understood relative to p53-dependent apoptosis. IR induces both p53-dependent and p53-independent apoptoses in Drosophila melanogaster, making studies of both modes of cell death possible in a genetically tractable model. Previous studies have found that Drosophila E2F proteins are generally pro-death or neutral with regard to p53-dependent apoptosis...
October 1, 2010: Developmental Biology
Brandon N Nicolay, Battuya Bayarmagnai, Nam Sung Moon, Elizaveta V Benevolenskaya, Maxim V Frolov
Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumor suppressor pathway, pRB functions to maintain the terminally differentiated state. We show that mutations in the Hippo signaling pathway, wts or hpo, trigger widespread dedifferentiation of rbf mutant cells in the Drosophila eye...
April 22, 2010: PLoS Genetics
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