The control of cell proliferation is of central importance
to the proper development of a multicellular organism,
the homeostatic maintenance of tissues, and the ability
of certain cell types to respond appropriately to
environmental cues. Disruption of normal cell growth
control underlies many pathological conditions including
the development of malignant tumors. Rapid advances
in defining the activities controlling cell growth
regulation have led to the delineation of a pathway
controlling the progression of cells out of quiescence,
through G1, and into S phase that involves the activation
of G1 cyclin-dependent kinases (cdk) that control
the activity of the Rb tumor suppressor and related
proteins. Additional work has shown that the ability
of Rb to function as a growth suppressor is largely
through the control of the E2F transcription factor.
E2F is now known to comprise a family of at least
five distinct DNA binding activities that play a critical
role in cell growth regulation through the activation
of a variety of genes that encode proteins important
for DNA replication and the induction of S phase.
Much of the work in our laboratory is focused on
understanding the role of E2F activity in cell growth
control. This work has shown that individual E2F family
members have distinct functions with respect to gene
activation and control of cell cycle progression.
Moreover, this work has also allowed a delineation
of the regulatory relationship of E2F activity to
other regulatory events associated with cell cycle
progression, including the demonstration of a cooperative
action of E2F and the cyclin E-dependent cdk2 kinase
in the induction of S phase.
In addition to the role of E2F as a signal for the
induction of S phase, our recent experiments have
shown that the E2F1 product acts as a signal for apoptosis
and coincides with an induction of p53 accumulation.
Finally, in collaboration with the laboratory of Robin
Wharton, we have also taken advantage of our isolation
of a Drosophila E2F homolog to explore the role of
E2F activity in cell cycle control during normal development
of fly tissues. These studies have shown that E2F
overexpression induces cells that are otherwise quiescent
to enter S phase and then undergo apoptosis, events
characteristic of the action of E2F in mammalian cells.
As such, these studies provide a rationale to further
explore the action of E2F in cell growth and cell
fate determination in a system that facilitates genetic
analysis of interacting components. Students participate
in all aspects of the research projects.
