David R Clemmons

David R. Clemmons, MD, is a UNC Lineberger Comprehensive Cancer Center member and Sarah Graham Kenan Professor of Medicine at UNC-Chapel Hill in the Department of Biochemistry and Biophysics.

Sarah Graham Kenan Professor of Medicine
UNC-Chapel Hill
Cancer Cell Biology

Area of interest

One of the central focuses of investigation in this laboratory is to define the mechanism by which insulin-like growth factors (IGFs) interact with specific binding proteins secreted by normal and tumor cell types. IGFs have been implicated in in vivo human studies in the development of breast, prostate and colon carcinoma. We have determined that several human tumor cell lines including breast carcinomas, glioblastomas, Wilms tumor, human uterine tumor cells and prostate carcinoma cell lines secrete specific high affinity insulin-like growth factor binding proteins. Some forms of these proteins are capable of binding IGF-I and preventing its association with receptors on the cell surface and thereby inhibiting cellular replication. In contrast, other forms are capable of potentiating cell surface receptor binding and the cellular DNA synthesis response to this growth factor. Since these binding proteins are synthesized constitutively, it is possible that their constitutive synthesis results in autocrine activation of tumor cell growth. The purpose of these studies is to identify each of the proteins that are being synthesized by the tumor cells and to determine if they regulate tumorigenesis. We have cloned and determined by cDNA-sequencing the amino acid sequence of all six forms of binding proteins. Likewise, we have determined that several post-translational modifications of these proteins including phosphorylation, proteolysis, and adherence to extracellular matrix, modify their ability to alter IGF-I action. In vitro mutagenesis has been used to create recombinant protesting that can each be tested for altered biologic activity. We are analyzing tumor cell products to determine if the forms of IGFBPs that are synthesized are altered and how these altered forms function in regulating cell growth.

A second major focus of research in our laboratory is to analyze the role of integrin receptors in controlling IGF-I action. We have determined that blocking of aVb3 occupancy by vitronectin or other extracellular matrix proteins results in attenuation of IGF-I mediated actions. All IGF-I mediated actions including stimulation of cell replication, protein synthesis and inhibition of apoptosis. This may be very important in the development of cancer since integrin can change during tumorigenesis. Further, we have determined that this block is exerted at the level of IGF-I receptor phosphorylation. That is, blocking integrin receptor occupancy results in direct inability of IGF-I to activate the tyrosine kinase activity of its own receptor and inhibition of phosphorylation of downstream signaling molecules such as IRS-1. Currently, we are investigating the molecular mechanism by which this inhibition occurs. Secondarily, we have determined that ligand occupancy of the a2b1 integrin has the opposite effect; that is, it inhibits IGF action, and blocking binding to a2b1 with an anti-integrin antibody stimulates IGF actions. We are currently trying to determine the point at which the IGF-I signal transduction pathway wherein a2b1 receptor occupancy interacts. These exciting studies offer the possibility of understanding how changes in integrin display may alter sensitivity to this growth factor which has been implicated in breast and prostate cancer.

Awards and Honors

2005 Aurbach Award, Endocrine Society
2004 MERIT Award National Institutes of Health

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