Functional Evolution of the Vertebrate Myb Gene Family

Davidson, Courtney; Tirouvanziam, Rabindra; Herzenberg, Leonard A.; Lipsick, Joseph S.

doi:10.1534/genetics.104.034132

Cited by 51 publications

(54 citation statements)

References 78 publications

(13 reference statements)

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“…These observations suggest that during the evolution of nematodes, there was a selection for a decoupling of Myb and the remaining members of the Myb-MuvB/dREAM complex. We have previously shown that vertebrate B-Myb can complement cell cycle defects in a Drosophila Myb-null mutant (41). Consistent with this observation, others have shown that vertebrate B-Myb is present in a complex together with the homologs of the MuvB core complex (42)(43)(44).…”

Section: Discussionsupporting

confidence: 68%

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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Section: Discussionsupporting

confidence: 68%

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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“…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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“…In vertebrates, there are three Myb family members: A-Myb, B-Myb, and c-Myb (4). Drosophila has a single Myb gene-the functional ortholog of B-Myb (5,6).…”

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confidence: 99%

The Complex Containing Drosophila Myb and RB/E2F2 Regulates Cytokinesis in a Histone H2Av-Dependent Manner

DeBruhl

Wen

Lipsick

2013

Molecular and Cellular Biology

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cIn Drosophila, mutation of the oncogene Myb reduced the expression of mitotic genes, such as polo and ial, and caused multiple mitotic defects, including disrupted chromosome condensation and abnormal spindles. We now show that binucleate cells, the hallmark phenotype of cytokinesis failure, accumulate in Myb-null ovarian follicle cell and wing disc epithelia. Myb functions as an activator in the generally repressive Drosophila RBF, E2F2, and Myb (dREAM)/Myb-MuvB complex. Absence of the dREAM subunit Mip130 or E2F2 suppressed the Myb-null cytokinesis defect. Therefore, we used Myb-null binucleate cells as a quantitative phenotypic readout of transcriptional repression by the dREAM complex. In the absence of Myb, the complex was sensitive to the dose of the subunits E2F2, Mip120, Caf1, and Lin-52 but not Mip130 or Mip40. Surprisingly, reduction of the dose of His2Av/H2A.z also suppressed the Myb-null binucleate cell phenotype, suggesting a novel role for this variant histone in transcriptional repression by the dREAM complex.

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Functional Evolution of the Vertebrate Myb Gene Family

Cited by 51 publications

References 78 publications

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

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

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

The Complex Containing Drosophila Myb and RB/E2F2 Regulates Cytokinesis in a Histone H2Av-Dependent Manner

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