Cancer is caused by mutations (alterations) in oncogenes and tumor suppressor genes. Much of what we know about the function of cancer-causing genes comes from studies of genetic model organisms like fruit flies and soil nematodes. This project focuses on the Myb oncoprotein and its interactions with a four-protein tumor suppressor complex called the MuvB core. The fruit fly is an excellent model for these studies because it has only one Myb gene, whereas vertebrate animals including humans have three related Myb genes. In particular, the human B-Myb gene that is associated with poor prognosis in human breast cancer is structurally similar to and can functionally replace the Myb gene of fruit flies. Previous work has shown that the MuvB tumor suppressor proteins prevent the expression of genes that promote cell division. The Myb protein directly interacts with the MuvB proteins, thereby permitting the expression of the genes that MuvB inhibits. A major goal of this proposal is to understand in molecular detail the mechanism by which Myb and MuvB regulate gene expression. The tools of genetics, biochemistry, and cell biology will be used to identify the changes in chromatin (DNA and associated proteins) that occur in the presence of Myb and MuvB. Another major goal is to understand exactly how the Myb and MuvB proteins interact with and regulate one another. A relatively small portion of the Myb protein is sufficient to interact with the MuvB proteins and inhibit their function. A better understanding of the precise structures that mediate this interaction may lead to the development of new small molecules that will be useful in the treatment of breast cancers with increased levels of B-Myb.
Mutations (alterations) in normal genes cause human cancer. The genes being studied in this project are known to be mutated in human breast cancer, leukemia, and lymphoma. The goal of the project is to understand how the proteins produced by these genes control cell division and cell identity, two properties of cells that are deranged in cancer.
|Guiley, Keelan Z; Iness, Audra N; Saini, Siddharth et al. (2018) Structural mechanism of Myb-MuvB assembly. Proc Natl Acad Sci U S A 115:10016-10021|
|Cheng, Mei-Hsin; Andrejka, Laura; Vorster, Paul J et al. (2017) The Drosophila LIN54 homolog Mip120 controls two aspects of oogenesis. Biol Open 6:967-978|
|Barasch, Nicholas; Gong, Xue; Kwei, Kevin A et al. (2017) Recurrent rearrangements of the Myb/SANT-like DNA-binding domain containing 3 gene (MSANTD3) in salivary gland acinic cell carcinoma. PLoS One 12:e0171265|
|Grigorian, Melina; DeBruhl, Heather; Lipsick, Joseph S (2017) The role of variant histone H2AV in Drosophila melanogaster larval hematopoiesis. Development 144:1441-1449|
|DeBruhl, Heather; Wen, Hong; Lipsick, Joseph S (2013) The complex containing Drosophila Myb and RB/E2F2 regulates cytokinesis in a histone H2Av-dependent manner. Mol Cell Biol 33:1809-18|
|Davidson, Colin J; Guthrie, Erin E; Lipsick, Joseph S (2013) Duplication and maintenance of the Myb genes of vertebrate animals. Biol Open 2:101-10|
|Lewis, Peter W; Sahoo, Debashis; Geng, Cuiyun et al. (2012) Drosophila lin-52 acts in opposition to repressive components of the Myb-MuvB/dREAM complex. Mol Cell Biol 32:3218-27|
|Sim, Choon Kiat; Perry, Sarah; Tharadra, Sana Khalid et al. (2012) Epigenetic regulation of olfactory receptor gene expression by the Myb-MuvB/dREAM complex. Genes Dev 26:2483-98|
|Ouyang, Yingshi; Petritsch, Claudia; Wen, Hong et al. (2011) Dronc caspase exerts a non-apoptotic function to restrain phospho-Numb-induced ectopic neuroblast formation in Drosophila. Development 138:2185-96|
|Andrejka, Laura; Wen, Hong; Ashton, Jonathan et al. (2011) Animal-specific C-terminal domain links myeloblastosis oncoprotein (Myb) to an ancient repressor complex. Proc Natl Acad Sci U S A 108:17438-43|
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