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kinases postdoctoral opportunity
I have postdoctoral positions available to examine biochemical mechanisms controlling the eukaryotic cell cycle. Our interests are events at the G1-S transition and the exit from mitosis, including the role of the Cdc14 phosphatase, cyclin E/Cdk2, and ubiquitin-dependent proteolysis. We have a large number of novel SCF ubiquitin ligases that have interesting roles in the cell cycle.
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Proteolytic and cell cycle control of the chromosome and centrosome cycles
Postdoctoral Fellow Positions, available September 1999
Peter Jackson, Stanford University School of Medicine
My laboratory has postdoctoral positions to study critical problems in the control of the cell cycle, the centrosome cycle, and DNA replication. Using mammalian tissue culture systems and the Xenopus embryo, our laboratory is trying to understand the biochemical mechanisms that gate the replication and segregation of the chromosomes and control the centrosome cycle. Several problems currently interest us:
1. Control of mitotic exit and G1 progression by the Cdc14 phosphatase.
Cdc14 is a dual-specificity phosphatase that dephosphorylates similar substrates to those phosphorylated by cyclin E/Cdk2 or cyclin B/Cdc2. We find that Cdc14 has a role in mitotic exit and in determining the length of G1 in Xenopus embryos and tissue culture cells. We have determined that Cdc14 restrains DNA replication both by dephosphorylating the p27 Cdk inhibitor and by restraining the nuclear accumulation of cyclin E/Cdk2. We have also uncovered a mechanism for Cdc14 inactivation that is important for cells to reenter S phase. We have characterized Cdc14 complexes and identified a number of novel molecular interactors for Cdc14. We are currently dissecting the critical mechanisms affecting Cdc14 and mitotic exit and the reentry into S phase. Several projects are possible including understanding the biochemical control of mitotic exit and testing how Cdc14 controls specific structural changes including nuclear reformation, spindle disassembly, chromosome decondensation and the licensing of DNA replication, and ultimately G1 progression in both embryos and in somatic cells.
2. SCF ubiquitin ligases in cell cycle control.
SCF ubiquitin ligases play critical roles in DNA replication and in other events of the cell cycle. We have recently discovered a role for SCF ubiqutiin ligases in the centrosome duplication cycle (see reference 8). Using several types of screens, our laboratory has identified over a dozen F-box genes in Xenopus and humans (Current Biology, in press). We are screening among these genes to determine which have critical roles in important cell cycle processes including DNA replication, the centrosome cycle, and the control of mitosis. We have already found one novel F-box protein important for DNA replication and another localized to the mitotic spindle poles and critical spindle function. Several projects are possible relating to the many proteins we now have in hand and their respective functions in the cell cycle, tumor suppression, and other physiologically interesting events.
3. Identifying the targets of cyclin E/Cdk2 and the SCF at the centrosome
We have defined roles for both cyclin E/Cdk2 and SCF ubiquitin ligases at the centrosome. We have begun to identify the targets of these regulators at the centrosome, using a variety of screens. For the cyclin E substrates, identification of the cyclin E/Cdk2 phosphorylation sites by mass spectrometry will allow us to construct and test the effect of overexpressing these mutants on the centrosome cycle. To define SCF substrates, we will use the specific F-box proteins at the centrosome to begin to probe for their associated substrates.
Selected references: (1) R. W. King, Jackson, P. K., and M. W. Kirschner (1994). Mitosis in Transition. Cell, 79, 563-571. (2) Jackson, P. K., S. Chevalier, M. Phillipe, and M. W. Kirschner (1995). Early events in DNA replication require cyclin E and are blocked by p21CIP1. J. Cell Biol. 130, 755-769. (3) Chen, J., P. K. Jackson, M. W. Kirschner, and A. Dutta (1995). Inhibition of cdk2 kinase, but not PCNA, is essential for the growth suppression activity of p21. Nature 374, 386-388 (4) Jackson, P. K. (1996). Cull and Destroy. Current Biology 6, 1209-1212. (5) Wolf, D. A. and P. K. Jackson, (1998). Oiling the gears of anaphase. Current Biology 8, 636-639. (6) Lacey, K., P. K. Jackson, and T. Stearns (1999). Cyclin-dependent kinases direct centrosome duplication. Proc. Natl. Acad. Sci 96, 2817-2822. (7) Wolf, D.A., McKeon, F., and P.K. Jackson (1999). F-box/WD-repeat proteins Pop1p and Popo2p form heterooligomeric complexes to bind and direct proteolytic destruction of Cdc18p. Current Biology 9, 373-376. (8) Freed, E., Lacey, K., P. Huey, S. Lyapina, R. Deshaies, T. Stearns, and P. K. Jackson (1999). SCF components Skp1 and Cul1 localize to and direct the duplication of the centrosome. Genes & Development, September 1 issue.
Stanford University School of Medicine
Departments of Pathology and Microbiology & Immunology
300 Pasteur Drive, MC 5324
Palo Alto, CA 94304-5324
650-498-6134 (Patty Winningham)