The long term objective of this project is to understand the processes that control mammalian cell growth, and how these processes are affected in the development of tumors. This includes the mechanisms by which growth factors can bind to the cell surface, transmit signals to the intracellular compartment and ultimately cause the cell to progress through mitosis. Mitogenic activation of quiescent cells involves multiple interacting signalling pathways that result in a number of immediate or early responses. In addition, other responses occur many hours after activation, after many of the early responses have subsided. Some of these late responses are obligatory for the cell to enter into the DNA synthetic phase of the cell cycle and an important, but little understood, question is the sequence of events that lead to their activation. This is a proposal to study the regulation of a vital late response to growth factor action: the elevated expression of transferrin receptors. Mitogenic stimulation of cells leads to a dramatic increase in the level of this receptor on the cell surface which occurs just before the onset of S phase. If the receptors are blocked at the cell surface, cell growth is prevented and the cells accumulate near the G1/S phase boundary. The increased expression of transferrin receptors that occurs during cell proliferation is associated with the transcriptional activation of its gene. Thus by examining the mechanisms that lead to this activation, some of the processes and pathways involved in regulating late events can be determined. First, the mitogen responsive elements in the regulatory region of the gene will be precisely mapped using a series of genetic constructs containing deletions an site- specific mutations. The transacting factors that act at these sites will be identified and then purified. The purified factors will be used to prepare immunological and genetic probes for the factors. Finally, using these probes and a number of specific growth factors and pharmacological reagents we will determine the effects of various signalling pathways on expression of the receptor gene and on the synthesis, transport, and post- translational modification of the transacting factors involved.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM043976-03
Application #
3303119
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1991-07-01
Project End
1993-03-31
Budget Start
1991-07-01
Budget End
1992-03-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of South Dakota
Department
Type
Schools of Arts and Sciences
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069