The research in our lab is focused on understanding the molecular mechanisms of the cell cycle regulation and how these mechanisms are utilized in vivo. Many models attribute a central role in cell cycle regulation to a transcriptional factor E2F and Retinoblastoma tumor suppressor protein (pRB). pRB is a founding member of a family of negative regulators of cell proliferation. In mammalian cells, there is a large number of related E2F and pRB family members and recent findings that these proteins have a role beyond the G1/S control complicate studying the function and regulation of these proteins in vivo. There is also a considerable debate over the mechanism by which pRB negatively controls cell proliferation and its tumor suppressor properties.

Figure 1. Mutations that rescue the proliferation defects induced by dE2F2/RBF. Mosaic eyes containing patches of wild type tissue (red) and mutant tissue (white) are shown. (A) Control experiment. Mutant (white) tissue does not proliferate due to the activity of dE2F2/RBF. The eye consists of entirely wild type tissue (red). (B-D) Randomly induced mutations overcome the dE2F2/RBF block to cell proliferation and allow the mutant tissue to proliferate giving rise to appearance of white tissue. Such mutations somehow inactivate the dE2F2/RBF complex. Our goal is to dissect the molecular mechanisms of their action in order to learn about function and regulation of the pRB pathway in vivo.

There has been a significant progress in recent years toward the understanding of the biochemical properties of E2F and pRB proteins and the ways they are regulated. Nevertheless, there is no agreement about the significance of these features in vivo. Apparently, our understanding of the role of E2F and pRB and their regulation in the context of a multicellular organism lags far behind the pace of their biochemical characterization. Drosophila has a streamlined version of the mammalian cell cycle regulation. This is attested by the functional conservation of the basic biochemical machinery that controls cell proliferation in flies and mammals. Our lab is carrying out large scale unbiased genetic screens to identify new genes that interface with the E2F/pRB module in vivo and contribute to its regulation during development. Given the pivotal role of pRB in tumor suppression, an understanding of how the function of the Drosophila homologues dE2F/pRB is regulated will provide crucial clues in understanding the regulation of mammalian cell growth and the ways in which such controls may go wrong in human cancer.