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Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers.
Song W, Hwang Y, Youngblood VM, Cook RS, Balko JM, Chen J, Brantley-Sieders DM
(2017) Oncogene 36: 5620-5630
MeSH Terms: Animals, Benzamides, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, Ephrin-A2, Female, Gene Knockdown Techniques, Humans, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Neoplasm Recurrence, Local, Niacinamide, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-myb, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added March 14, 2018
Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of breast cancer, and disproportionally affects young premenopausal women and women of African descent. Patients with TNBC suffer a poor prognosis due in part to a lack of molecularly targeted therapies, which represents a critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for TNBC. EphA2 expression is enriched in the basal-like molecular subtype in human breast cancers. Loss of EphA2 function in both human and genetically engineered mouse models of TNBC reduced tumor growth in culture and in vivo. Mechanistically, targeting EphA2 impaired cell cycle progression through S-phase via downregulation of c-Myc and stabilization of the cyclin-dependent kinase inhibitor p27/KIP1. A small molecule kinase inhibitor of EphA2 effectively suppressed tumor cell growth in vivo, including TNBC patient-derived xenografts. Thus, our data identify EphA2 as a novel molecular target for TNBC.
0 Communities
2 Members
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20 MeSH Terms
Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression.
Kasper LH, Fukuyama T, Lerach S, Chang Y, Xu W, Wu S, Boyd KL, Brindle PK
(2013) PLoS One 8: e82684
MeSH Terms: Animals, Blood Cells, CREB-Binding Protein, Cells, Cultured, E1A-Associated p300 Protein, Epistasis, Genetic, Hematopoiesis, Mice, Mice, Knockout, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myb
Show Abstract · Added March 20, 2014
Adult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, mice homozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesis that the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb. We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains of CBP and p300, and measured the effect of KIX domain mutations on c-Myb-dependent gene expression. We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, B cells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blood defects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, we demonstrated that the CBP and p300 KIX domains contribute to both c-Myb-dependent gene activation and repression. Together these results suggest that the KIX domains of CBP, and especially p300, are principal mediators of c-Myb-dependent gene activation and repression that is required for definitive hematopoiesis.
1 Communities
1 Members
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11 MeSH Terms
Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans.
Bae HT, Baldwin CT, Sebastiani P, Telen MJ, Ashley-Koch A, Garrett M, Hooper WC, Bean CJ, Debaun MR, Arking DE, Bhatnagar P, Casella JF, Keefer JR, Barron-Casella E, Gordeuk V, Kato GJ, Minniti C, Taylor J, Campbell A, Luchtman-Jones L, Hoppe C, Gladwin MT, Zhang Y, Steinberg MH
(2012) Blood 120: 1961-2
MeSH Terms: African Americans, Anemia, Sickle Cell, Carrier Proteins, DNA, Intergenic, Fetal Hemoglobin, Genetic Variation, Genome-Wide Association Study, Humans, Nuclear Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myb
Added November 27, 2013
1 Communities
1 Members
0 Resources
11 MeSH Terms
Identification of a Drosophila Myb-E2F2/RBF transcriptional repressor complex.
Lewis PW, Beall EL, Fleischer TC, Georlette D, Link AJ, Botchan MR
(2004) Genes Dev 18: 2929-40
MeSH Terms: Animals, Chromatography, Gel, Drosophila, Drosophila Proteins, E2F2 Transcription Factor, Immunoprecipitation, Proto-Oncogene Proteins c-myb, Repressor Proteins, Retinoblastoma Protein, Transcription Factors
Show Abstract · Added February 20, 2015
The Drosophila Myb complex has roles in both activating and repressing developmentally regulated DNA replication. To further understand biochemically the functions of the Myb complex, we fractionated Drosophila embryo extracts relying upon affinity chromatography. We found that E2F2, DP, RBF1, RBF2, and the Drosophila homolog of LIN-52, a class B synthetic multivulva (synMuv) protein, copurify with the Myb complex components to form the Myb-MuvB complex. In addition, we found that the transcriptional repressor protein, lethal (3) malignant brain tumor protein, L(3)MBT, and the histone deacetylase, Rpd3, associated with the Myb-MuvB complex. Members of the Myb-MuvB complex were localized to promoters and were shown to corepress transcription of developmentally regulated genes. These and other data now link together the Myb and E2F2 complexes in higher-order assembly to specific chromosomal sites for the regulation of transcription.
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1 Members
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10 MeSH Terms
Proteomics analysis reveals stable multiprotein complexes in both fission and budding yeasts containing Myb-related Cdc5p/Cef1p, novel pre-mRNA splicing factors, and snRNAs.
Ohi MD, Link AJ, Ren L, Jennings JL, McDonald WH, Gould KL
(2002) Mol Cell Biol 22: 2011-24
MeSH Terms: Amino Acid Sequence, Animals, Cell Cycle Proteins, Humans, Macromolecular Substances, Mass Spectrometry, Microscopy, Electron, Molecular Sequence Data, Molecular Weight, Multiprotein Complexes, Mutation, Proteome, Proto-Oncogene Proteins c-myb, RNA Precursors, RNA Splicing, RNA, Messenger, RNA, Small Nuclear, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Homology, Amino Acid, Thermodynamics
Show Abstract · Added April 18, 2013
Schizosaccharomyces pombe Cdc5p and its Saccharomyces cerevisiae ortholog, Cef1p, are essential Myb-related proteins implicated in pre-mRNA splicing and contained within large multiprotein complexes. Here we describe the tandem affinity purification (TAP) of Cdc5p- and Cef1p-associated complexes. Using transmission electron microscopy, we show that the purified Cdc5p complex is a discrete structure. The components of the S. pombe Cdc5p/S. cerevisiae Cef1p complexes (termed Cwfs or Cwcs, respectively) were identified using direct analysis of large protein complex (DALPC) mass spectrometry (A. J. Link et al., Nat. Biotechnol. 17:676-682, 1999). At least 26 proteins were detected in the Cdc5p/Cef1p complexes. Comparison of the polypeptides identified by S. pombe Cdc5p purification with those identified by S. cerevisiae Cef1p purification indicates that these two yeast complexes are nearly identical in composition. The majority of S. pombe Cwf proteins and S. cerevisiae Cwc proteins are known pre-mRNA splicing factors including core Sm and U2 and U5 snRNP components. In addition, the complex contains the U2, U5, and U6 snRNAs. Previously uncharacterized proteins were also identified, and we provide evidence that several of these novel factors are involved in pre-mRNA splicing. Our data represent the first comprehensive analysis of CDC5-associated proteins in yeasts, describe a discrete highly conserved complex containing novel pre-mRNA splicing factors, and demonstrate the power of DALPC for identification of components in multiprotein complexes.
0 Communities
4 Members
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24 MeSH Terms
Evidence that Myb-related CDC5 proteins are required for pre-mRNA splicing.
Burns CG, Ohi R, Krainer AR, Gould KL
(1999) Proc Natl Acad Sci U S A 96: 13789-94
MeSH Terms: 3T3 Cells, Animals, Cell Cycle Proteins, Cell Nucleus, Fungal Proteins, Humans, Mice, Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myb, RNA Precursors, RNA Splicing, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Spliceosomes, Subcellular Fractions
Show Abstract · Added March 5, 2014
The conserved CDC5 family of Myb-related proteins performs an essential function in cell cycle control at G(2)/M. Although c-Myb and many Myb-related proteins act as transcription factors, herein, we implicate CDC5 proteins in pre-mRNA splicing. Mammalian CDC5 colocalizes with pre-mRNA splicing factors in the nuclei of mammalian cells, associates with core components of the splicing machinery in nuclear extracts, and interacts with the spliceosome throughout the splicing reaction in vitro. Furthermore, genetic depletion of the homolog of CDC5 in Saccharomyces cerevisiae, CEF1, blocks the first step of pre-mRNA processing in vivo. These data provide evidence that eukaryotic cells require CDC5 proteins for pre-mRNA splicing.
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2 Members
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20 MeSH Terms
Diverse developing mouse lineages exhibit high-level c-Myb expression in immature cells and loss of expression upon differentiation.
Ess KC, Witte DP, Bascomb CP, Aronow BJ
(1999) Oncogene 18: 1103-11
MeSH Terms: Age Factors, Animals, Cell Differentiation, Digestive System, Embryonic and Fetal Development, Hair Follicle, In Situ Hybridization, Liver, Mice, Mitosis, Odontogenesis, Oncogenes, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myb, Thymus Gland, Thyroid Gland, Trachea, Trans-Activators
Show Abstract · Added June 9, 2010
The c-myb gene encodes a sequence specific transactivator that is required for fetal hematopoiesis, but its potential role in other tissues is less clear because of the early fetal demise of mice with targeted deletions of the c-myb gene and incomplete of knowledge about c-myb's expression pattern. In the hematopoietic system, c-Myb protein acts on target genes whose expression is restricted to individual lineages, despite Myb's presence and role in multiple immature lineages. This suggests that c-Myb actions within different cell type-specific contexts are strongly affected by combinatorial interactions. To consider the possibility of similar c-Myb actions could extend into non-hematopoietic systems in other cell and tissue compartments, we characterized c-myb expression in developing and adult mice using in situ hybridization and correlated this with stage-specific differentiation and mitotic activity. Diverse tissues exhibited strong c-myb expression during development, notably tooth buds, the thyroid primordium, developing trachea and proximal branching airway epithelium, hair follicles, hematopoietic cells, and gastrointestinal crypt epithelial cells. The latter three of these all maintained high expression into adulthood, but with characteristic restriction to immature cell lineages prior to their terminal differentiation. In all sites, during fetal and adult stages, loss of c-Myb expression correlated strikingly with the initiation of terminal differentiation, but not the loss of mitotic activity. Based on these data, we hypothesize that c-Myb's function during cellular differentiation is both an activator of immature gene expression and a suppressor of terminal differentiation in diverse lineages.
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1 Members
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18 MeSH Terms
Myb-related Schizosaccharomyces pombe cdc5p is structurally and functionally conserved in eukaryotes.
Ohi R, Feoktistova A, McCann S, Valentine V, Look AT, Lipsick JS, Gould KL
(1998) Mol Cell Biol 18: 4097-108
MeSH Terms: Amino Acid Sequence, Animals, Biological Evolution, Caenorhabditis elegans, Cell Cycle Proteins, Drosophila melanogaster, Eukaryotic Cells, Fungal Proteins, G2 Phase, Genetic Complementation Test, Humans, Mitosis, Molecular Sequence Data, Mutagenesis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myb, RNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Homology, Amino Acid, Temperature, Trans-Activators, Transcription Factors, Transcription, Genetic, Up-Regulation
Show Abstract · Added March 5, 2014
Schizosaccharomyces pombe cdc5p is a Myb-related protein that is essential for G2/M progression. To explore the structural and functional conservation of Cdc5 throughout evolution, we isolated Cdc5-related genes and cDNAs from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens. Supporting the notion that these Cdc5 gene family members are functionally homologous to S. pombe cdc5(+), human and fly Cdc5 cDNAs are capable of complementing the temperature-sensitive lethality of the S. pombe cdc5-120 mutant. Furthermore, S. cerevisiae CEF1 (S. cerevisiae homolog of cdc5(+)), like S. pombe cdc5(+), is essential during G2/M. The location of the cdc5-120 mutation, as well as mutational analyses of Cef1p, indicate that the Myb repeats of cdc5p and Cef1p are important for their function in vivo. However, we found that unlike in c-Myb, single residue substitutions of glycines for hydrophobic residues within the Myb repeats of Cef1p, which are essential for maintaining structure of the Myb domain, did not impair Cef1p function in vivo. Rather, multiple W-to-G substitutions were required to inactivate Cef1p, and many of the substitution mutants were found to confer temperature sensitivity. Although it is possible that Cef1p acts as a transcriptional activator, we have demonstrated that Cef1p is not involved in transcriptional activation of a class of G2/M-regulated genes typified by SWI5. Collectively, these results suggest that Cdc5 family members participate in a novel pathway to regulate G2/M progression.
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2 Members
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26 MeSH Terms
Winner of the Theodore E. Woodward Award: c-Myb and the coordinate regulation of thymic genes.
Hutton JJ, Ess KC, Witte DP, Aronow BJ
(1996) Trans Am Clin Climatol Assoc 107: 115-24
MeSH Terms: Adenosine Deaminase, Animals, Awards and Prizes, Base Sequence, DNA, Embryonic and Fetal Development, Gene Expression Regulation, Developmental, Hematopoiesis, Humans, Molecular Sequence Data, Oncogenes, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myb, RNA, Messenger, Societies, Medical, Thymus Gland, Trans-Activators, United States
Added June 9, 2010
0 Communities
1 Members
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18 MeSH Terms
The Schizosaccharomyces pombe cdc5+ gene encodes an essential protein with homology to c-Myb.
Ohi R, McCollum D, Hirani B, Den Haese GJ, Zhang X, Burke JD, Turner K, Gould KL
(1994) EMBO J 13: 471-83
MeSH Terms: Amino Acid Sequence, Base Sequence, Cell Cycle Proteins, Cloning, Molecular, DNA Replication, DNA, Fungal, DNA-Binding Proteins, Fungal Proteins, Genes, Fungal, Genetic Complementation Test, Hydroxyurea, Molecular Sequence Data, Phenotype, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-myb, Restriction Mapping, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Sequence Homology, Amino Acid
Show Abstract · Added March 5, 2014
The Schizosaccharomyces pombe cdc5+ gene was identified in the first screen for cell division cycle mutants in this yeast. The cdc5+ gene was reported to be required for nuclear division but because of its modest elongation and leaky nature at the non-permissive temperature, it was not investigated further. Here, we report the characterization of the single allele of this gene, cdc5-120, in more detail. The mutant arrests with a 2N DNA content and a single interphase nucleus. Further genetic analyses suggest that cdc5+ gene function is essential in the G2 phase of the cell cycle. We have cloned and sequenced the cdc5+ gene. The deduced protein sequence predicts that Cdc5 is an 87 kDa protein and contains a region sharing significant homology with the DNA binding domain of the Myb family of transcription factors. Deletion mapping of the cdc5+ gene has shown that the N-terminal 232 amino acids of the protein, which contain the Myb-related region, are sufficient to complement the cdc5ts strain. A cdc5 null mutant was generated by homologous recombination. Haploid cells lacking cdc5+ are inviable, indicating that cdc5+ is an essential gene. A fusion protein consisting of bacterial glutathione S-transferase joined in-frame to the N-terminal 127 amino acids of the Cdc5 protein is able to bind to DNA cellulose at low salt concentrations. This evidence suggests that cdc5+ might encode a transcription factor whose activity is required for cell cycle progression and growth during G2.
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19 MeSH Terms