Joan Ruderman

Department of Cell Biology
Harvard Medical School
Building C2, Room 428
240 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-1104
Fax: (617) 432-0555
Email: ruderman@hms.harvard.edu
Web Page: The Ruderman Lab Page
3 postdoctoral fellows, 5 graduate students, 2 research assistants, 1 undergraduate

My lab is investigating some of the basic molecular mechanisms that regulate cell cycle progression in vertebrate cells. Much of our work uses Xenopus eggs, which provide especially suitable experimental material for molecular, biochemical and cytological approaches to basic questions of cell cycle regulation. Many of these questions are being addressed using concentrated cell-free extracts that retain the ability to progress through two or more full cell division cycles in vitro.

Work over the past 20 years has revealed how cyclin-dependent kinases control the G2/M transition and how their activity is, in turn, controlled by several checkpoint pathways. By contrast, much less is known about the roles of, and molecular mechanisms that regulate, several other kinases that have important mitotic roles. One of these is Aurora-A (Aur-A), a 46 kDa ser/thr kinase that is required for the G2/M transition, formation of a functional bipolar spindle and accurate chromosome segregation. Sight increases in Aur-A protein levels rapidly generate aneuploid cells with multiple spindle poles, and sustained overexpression is oncogenic. In humans, the Aur-A gene is amplified and/or overexpressed in many kinds of cancers. We are in the process of understanding the mechanisms that regulate the Aur-A activation during the G2/M transition and the destruction of Aur-A protein during mitotic exit.

In a second area, we are investigating two regulators of cdc2/cyclin B/cdc2 activation at the G2/M transition: Wee1, the tyrosine kinase that phosphorylates and inhibits cyclin B/cdc2 during G2, and Cdc25, the tyrosine phosphatase that dephosphorylates and activates cyclin B/cdc2 at G2/M. Work in the Xenopus egg extract system has continued to reveal new and surprising features of this iconic regulatory pathway.

We recently began a new project on endocrine disruptors, compounds that mimic or block the ability of steroid hormones to regulated proliferation and differentiation. Many pesticides, herbicides, fungicides and industrial pollutants are now know to act as endocrine disruptors. Such chemicals have profound effects on sexual development and behavior of many species. Some of these stimulate the proliferation of hormone-dependent breast cancer and prostate cancer cells. Estrogen disruptors, such as the common insecticide DDT, were the first to be identified. Other known disruptors include methoxychlor, an insecticide in current use against mosquitoes, the commonly used plasticizers bisphenol A and phthalates, and the herbicide atrazine. We are exploring the use of Xenopus ovary explants and isolated oocytes as sensitive bioassay systems for endocrine disruptors. We are also trying to develop simple, rapid and highly sensitive in vitro assays that use recombinant fusion proteins to detect the presence and concentration of hormonally active compounds in the environment, as well as in everyday household and personal care products.

References:

• Littlepage, L. E., Wu, H., Andresson, T., Deanehan, J. K., Amundadottir, L. T., and Ruderman, J. V. (2002). Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A. Proc Natl Acad Sci U S A 99, 15440-15445.
• Littlepage, L. E., and Ruderman, J. V. (2002). Identification of a new APC/C recognition domain, the A box, which is required for the Cdh1-dependent destruction of the kinase Aurora-A during mitotic exit. Genes Dev 16, 2274-2285.
• Stanford, J. S., Lieberman, S. L., Wong, V. L., and Ruderman, J. V. (2003). Regulation of the G2/M transition in oocytes of Xenopus tropicalis. Dev Biol 260, 438-448.