by duplicating their genomes and other components and then distributing
these components equally into two daughter cells. The carefully
orchestrated series of events that leads to cell duplication and
division is called the cell cycle. Cell-cycle events are timed and
coordinated by a network of regulatory proteins called the cell-cycle
goal is a detailed biochemical understanding of the proteins that
make up the cell-cycle control system. Much of our work has focused
on the cyclin-dependent protein kinases (Cdks). These highly conserved
enzymes are activated at specific cell cycle stages and are directly
responsible for triggering major cell cycle events such as DNA replication
We use a variety
of different model systems, including budding yeast and mammalian
cells, to address fundamental questions in the control of cell division
by Cdks and other regulatory molecules. Major projects in the lab
include the following:
of the Cdks: Little
is known about the mechanisms by which Cdks trigger cell-cycle events.
It is generally assumed that Cdks, like other protein kinases, exert
their effects by phosphorylating target proteins, but few of these
target proteins have been identified. We are using a novel 'chemical
genetic' approach, conceived by our UCSF colleague Kevan
Shokat, to search the yeast and vertebrate proteomes
for Cdk substrates.
Exit from mitosis: We are exploring the regulatory
mechanisms that complete the cell cycle in late mitosis. Much of
this work focuses on a mysterious multi-subunit enzyme called the
Anaphase-promoting complex (APC). The APC is a ubiquitin-protein
ligase that catalyzes the attachment of the protein ubiquitin to
substrate proteins, thereby targeting these substrates for destruction.
In late mitosis, the APC triggers the proteolytic destruction of
several cell-cycle regulators, including cyclins. We are interested
in the biochemical reactions catalyzed by the APC and in the regulatory
systems that control these reactions.