Regulation of cell cycle in Drosophila melanogaster
	Iain Dawson, Ph.D. Lecturer and Associate Research Scientist Room: KBT 1103 Phone: (203) 432-6265 Email: iain.dawson@yale.edu

In my lab we use the fruit fly Drosophila melanogaster to study various aspects of cellular and developmental biology. Currently, my main effort is focused on using Drosophila to better understand the regulation of the cell division cycle, and in particular how progress through mitosis is controlled and coordinated.

Flies are an excellent system for such studies. Flies have wonderful genetic tools which provide a powerful means to identify and analyze genes involved in cell-cycle regulation. From a cell-cycle point of view, flies are higher eukaryotes - meaning they are grouped with vertebrate mammals such as ourselves in terms of their cell-cycle mechanics and regulation. Not surprisingly therefore, flies and humans possess a repertoire of cell-cycle regulatory genes and proteins which are structurally and functionally very analogous to each other. Moreover, because both organisms are multicellular, their cell-cycles are subject to the kinds of developmental and physiological constraints and regulatory pathways not found in unicellular organisms. Taken together these observations suggest flies can serve as a model system to gain valuable insights into cell-cycle processes which have human health implications such as the development of cancers and their treatment.

This is the primary reason we are studying the molecular mechanisms regulating mitotic progress in Drosophila. Our work with the fly cell-cycle gene fizzy (fzy) showed fzy to be an essential component of a specialized protein degradation pathway, termed Anaphase Promoting Complex (APC)-dependent proteolytic pathway, which is activated during mitosis. The fzy gene encodes a small WD40-repeat containing protein which binds directly to the APC and is essential for APC proteolytic activity, possibly acting as a docking module linking the APC complex to its substrates. APC-dependent proteolysis is responsible for degrading specific mitotic regulatory proteins which allows 1) anaphase to initiate and chromosomes to segregate, and 2) the events of late mitosis, such as chromosome decondensation and nuclear envelope reformation, to proceed. Failure to properly regulate APC activity can lead to genetic instability by chromosome loss during mitosis, which has been implicated in contributing to increased malignancy, and consequently poorer prognosis, in a number of cancers. However, disruption of APC-dependent proteolysis also offers exciting new possibilities for treating cancer. The very promising new mitosis-inhibiting, anti-neoplastic drug taxol (paclitaxel), works by binding to microtubules and disrupting the mitotic spindle, which indirectly leads to inhibition of APC dependent proteolysis pathway via a checkpoint mechanism. This can result in cells arresting in mitosis and entering an apoptotic pathway leading to cell death.

We have developed Drosophila strains in which the APC pathway is inappropriately over-activated in the developing eye by controlled miss-expression of the APC regulators fzy and fizzy-related (fzr). These flies are being used in genetic screens to identify genes which function to regulate APC activity during mitosis. The goal of this work is to identify the repertoire of genes/proteins and elucidate the regulatory hierarchies which control APC activation during the cell-cycle with the hope that this information may help identify better strategies and/or new targets for clinical intervention during cancer treatment.

In addition to cell-cycle control, we are also interested in how coordinated cell shape changes bring about large-scale tissue reorganization during development. To this end we have begun to examine the functions of dachshund, a gene which is required for normal morphogenesis and development of the Drosophila leg

Selected Publications

Dawson, I. A., Roth, S., Akam, M. and Artavanis-Tsakonas, S. (1993). Mutations of the fizzy locus cause metaphase arrest in Drosophila melanogaster embryos. Development 117:359-376.

Dawson, I. A., Roth, S. and Artavanis-Tsakonas, S. (1995). The Drosophila cell cycle gene fizzy is required for normal degradation of cyclins A and B during mitosis and has homology to the CDC20 gene of Saccharomyces cerevisiae. J Cell Biolt 129:725-737.

Fehon, R. G., Dawson, I. A. and Artavanis-Tsakonas, S. (1994). A Drosophila homologue of membrane-skeleton protein 4.1 is associated with septate junctions and is encoded by the coracle gene. Development 120:545-557.

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