Project Details


DESCRIPTION: Tumor necrosis factor-alpha (TNF) influences a wide variety of
cellular functions, including cell growth, cell death and metastases.
Although the action of TNF is mediated through its cell surface receptors,
the intracellular events that link ligand binding to the cytotoxic action of
TNF remain elusive. The overall objective of this grant application is to
define the signaling mechanisms that regulate TNF-mediated cell killing.
Signaling through TNF receptors (TNFR) is unique. They do not possess any
intrinsic kinase activity. It is presumed that upon ligand binding TNFR
activate and/or recruit other factors or kinases to convey its signal. The
specific focus of this project is to define the functional significance of
protein phosphorylation and dephosphorylation in TNF signaling. TNF
inhibits the growth of breast cancer cells in vitro but little is known
regarding the involvement of TNF in breast cancer pathogenesis. The protein
kinase C signal transduction pathway appears to regulate TNF sensitivity in
breast cancer cells. The specific aims of this application are to determine
the contribution of PKC isozymes in TNF-mediated cell death, to study the
regulation of TNFR function by kinases, to investigate their involvement on
the down-stream signaling events of TNF and to determine the basis for TNF
resistance in normal and malignant mammary cells.
Effective start/end date4/09/9728/02/10