Drosophila myb is required for the G2/M transition and maintenance of diploidy

Al, Katzen; Jackson, Jeffrey J.; Bp, Harmon; Sm, Fung; Ramsay, Gary; Jm, Bishop

doi:10.1101/gad.12.6.831

Cited by 70 publications

(74 citation statements)

References 56 publications

(94 reference statements)

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“…A further argument for a unique function of B-Myb is provided by recent work on Drosophila melanogaster. Drosophila has a single myb gene (Dm-myb) that has been implicated in cell proliferation and in controlling the activity of certain origins of DNA replication (Katzen et al, 1998;Beall et al, 2002;Fitzpatrick et al, 2002). Recent work has shown that B-myb, but not A-myb or c-myb, is able to complement a defective Dm-myb gene (Davidson et al, 2004), suggesting a unique and probably ancestral function for B-myb, which cannot be complemented by other vertebrate myb family members.…”

Section: Discussionmentioning

confidence: 99%

Disruption of B-myb in DT40 cells reveals novel function for B-Myb in the response to DNA-damage

et al. 2005

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B-Myb is a highly conserved vertebrate member of the Myb transcription factor family, which is expressed in virtually all proliferating cells. A large body of evidence suggests that B-Myb plays an important role in cell cycle regulation; however, the exact nature of its function has not yet been clarified. We have used gene targeting in chicken DT40 cells, a cell line exhibiting very high rates of homologous recombination, to create cells expressing endogenous B-myb in a doxycyclin-dependent manner. We find that the cells proliferate well in the absence of B-Myb, suggesting that B-Myb is not essential for cell proliferation per se. However, cells lacking B-Myb are more sensitive to DNA-damage induced by UV-irradiation and alkylation. Our work provides the first direct evidence for a novel function of B-Myb in the response to DNA-damage. The cells described here should be a useful model to characterize this function in more detail.

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Section: Discussionmentioning

confidence: 99%

Disruption of B-myb in DT40 cells reveals novel function for B-Myb in the response to DNA-damage

et al. 2005

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“…Two of these mutants (KW606AA and DQ617AA) were capable of rescuing weakly at 18°C when expressed via the native Myb promoter, implying that these mutant proteins themselves are heat-sensitive. Interestingly, the heat-sensitive hypomorphic Myb 1 mutant has a single amino acid substitution in the same highly conserved animal-specific region of the protein (G613S) (34) (Fig. 1).…”

Section: Evolutionarily Guided Alanine Substitution Mutants Of Drosopmentioning

confidence: 99%

Animal-specific C-terminal domain links myeloblastosis oncoprotein (Myb) to an ancient repressor complex

Andrejka

Wen

Ashton

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Members of the Myb oncoprotein and E2F-Rb tumor suppressor protein families are present within the same highly conserved multiprotein transcriptional repressor complex, named either as Myb and synthetic multivuval class B (Myb-MuvB) or as Drosophila Rb E2F and Myb-interacting proteins (dREAM). We now report that the animal-specific C terminus of Drosophila Myb but not the more highly conserved N-terminal DNA-binding domain is necessary and sufficient for (i) adult viability, (ii) proper localization to chromosomes in vivo, (iii) regulation of gene expression in vivo, and (iv) interaction with the highly conserved core of the MuvB/dREAM transcriptional repressor complex. In addition, we have identified a conserved peptide motif that is required for this interaction. Our results imply that an ancient function of Myb in regulating G2/M genes in both plants and animals appears to have been transferred from the DNA-binding domain to the animal-specific C-terminal domain. Increased expression of B-MYB/MYBL2, the human ortholog of Drosophila Myb, correlates with poor prognosis in human patients with breast cancer. Therefore, our results imply that the specific interaction of the C terminus of Myb with the MuvB/dREAM core complex may provide an attractive target for the development of cancer therapeutics.oncogene | transcription | repression | evolution T he Myb oncogene family was discovered because of the retroviral transduction of the chicken cellular myb protooncogene that generated the avian myeloblastosis virus (1, 2). Both the cellular Myb and viral Myb proteins are present within the nucleus of the cell, bind to specific DNA sequences, and can regulate gene expression (3-9). The Myb DNA-binding domain is present in members of all major classes of eukaryotic organisms, including plants, animals, fungi, cellular slime molds, and protists (10, 11). Simpler plants have only one or a few Myb transcription factors, whereas all flowering plant species have hundreds of related Myb transcription factors that arose via massive gene duplication and divergence (12). The picture in animals is simpler. All vertebrates have three closely related Myb transcription factors, whereas most invertebrates have only one Myb transcription factor. In addition to the presence of an aminoterminal Myb DNA-binding domain, most of these Myb transcription factors of animals share a conserved C-terminal domain that appears to be animal-specific. We have recently reported that, rather surprisingly, this C-terminal Myb domain is sufficient to rescue the lethality of a Myb null mutation in Drosophila when expressed via a heterologous promoter (13). We have now used a combination of genetic, cell biological, and biochemical approaches to explore the function of this animal-specific C-terminal Myb domain. We find that this domain is both necessary and sufficient for interaction with the synthetic multivulval class B (MuvB) core, a highly conserved transcriptional repressor complex that also interacts with the E2F-Rb tumor suppressor proteins (14-16...

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“…In contrast to vertebrates, a single myb gene has been found in Drosophila (10). The dm-myb gene regulates the G 2 ͞M transition, maintains normal ploidy and spindle formation, and plays a role in DNA synthesis (11)(12)(13)(14)(15). Interestingly, recent evidence has shown that knockdown of human B-myb leads to a reduction of cyclin B and cdc2 expression, suggesting that mammalian B-myb may be involved in G 2 ͞M regulation as well (16).…”

mentioning

confidence: 99%

A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility

Shepard

Amatruda

Stern

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

154

157

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A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative protooncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Geneexpression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.cell cycle

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Drosophila myb is required for the G2/M transition and maintenance of diploidy

Cited by 70 publications

References 56 publications

Disruption of B-myb in DT40 cells reveals novel function for B-Myb in the response to DNA-damage

Disruption of B-myb in DT40 cells reveals novel function for B-Myb in the response to DNA-damage

Animal-specific C-terminal domain links myeloblastosis oncoprotein (Myb) to an ancient repressor complex

A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility

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