Medical Student Research Fellowship for Summer 2006

Mentor: Marc Mumby, Ph.D.
Department: Pharmacology
Room number: ND7.502A
Mail Code: 9041
Phone number: 214-645-6152
E-mail: marc.mumby@utsouthwestern.edu
Project title: The role of PP2A in regulating DNA replication

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable):

Project Type basic research

Brief Description of Project:

The cell division control protein 6 (Cdc6) is essential for formation of pre-replication complexes at origins of DNA replication. Phosphorylation of Cdc6 by cyclin-dependent kinases regulates its stability and subcellular localization. Previous studies implicated protein phosphatase 2A (PP2A) in dephosphorylation of Cdc6. Experiments described here show that the PR70 (formerly PR48) member of the PPP2R3 family of regulatory subunits targets PP2A to Cdc6 in vitro and in vivo. The interaction with Cdc6 was mediated by residues within the carboxyl-terminus of PR70, while interaction with PP2A required N-terminal sequences conserved within the PPP2R3 family. Two functional EF-hand calcium-binding motifs that mediate a calcium-enhanced interaction of PR70 with PP2A were identified. Calcium had no effect on the interaction of PR70 with Cdc6, but enhanced the association of PP2A with Cdc6 through its effects on PR70. Calcium also enhanced the rate of Cdc6 dephosphorylation by a recombinant form of PP2A containing PR70. These observations provide evidence for a novel calcium-regulated mechanism for controlling PP2A activity and dephosphorylation of Cdc6. The goal of this project will be to determine the role of this interaction in intact cells.

Previous Research Activities or Publications with Medical Students:

I have had one previous summer Med Student. All pubs are with M.D./Ph.D. students.

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