Joseph Lipsick

Research/Lab website:   Myb World (Lipsick Lab Homepage)

Our laboratory studies the structure and function of chromosomes in metazoans. The Myb protein family provides us with a useful window for exploring chromosome biology because proteins that contain Myb domains play essential roles in telomere maintenance, centromere maintenance, nucleosome assembly and remodeling, and histone modification. The Myb gene family was first recognized in the form of the v-Myb oncogene of the avian myeloblastosis virus. This acutely transforming retrovirus causes rapidly fatal monoblastic leukemia in chickens. The normal c-Myb gene is expressed at high levels in immature blood cells and is essential for hematopoiesis in the laboratory mouse. Two additional Myb genes (A-Myb and B-Myb) appear to be present in all vertebrates. Increased expression of these three Myb genes is often seen in different types of human cancers. The Myb gene family has been conserved in animals, plants, fungi, and cellular slime molds. The Myb proteins contain tandem repeats of a ~50 amino acid helix-turn-helix motif, bind to specific DNA sequences, and can regulate gene expression. In a number of cases, the proteins encoded by this ancient gene family have been shown to act as key regulators of growth and development. Furthermore the Myb motif is present in a number of proteins that regulate chromosomal structure and function, including the major telomere-binding proteins, subunits of the major histone acetylase and deactylase complexes, and subunits of ATP-dependent chromatin remodeling machines.

For the past fifteen years, our laboratory has primarily focused on understanding the structure and function of v-Myb and c-Myb using the avian embryo as a model system. We developed the first assays for oncogenic transformation by molecular clones of this gene family. We then showed that truncation of the c-Myb protein is required for efficient oncogenic transformation and that these truncations alter DNA binding and transcriptional regulation. However, at present the animal Myb genes have not been placed in a genetic pathway. Specifically, the key upstream regulators, interacting proteins, and key downstream targets remain to be identified. Therefore, in addition to biochemical and viral genetic approaches to these problems, we are also using both the laboratory mouse and Drosophila melanogaster as model genetic systems for understanding the Myb pathways in animals. In this regard, we have recently generated two null alleles of Drosophila Myb. We have shown that loss of this gene causes mitotic arrest with aneuploidy, polyploidy, and spindle abnormalities. We have also collaborated with Mike Botchan’s lab at UC Berkeley to demonstrate that Dm-Myb is required for chorion gene amplification in Drosophila, the best studied model for site-specific DNA replication in higher eukaryotes.