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Mechanism of TGF-a shedding in lung cancer development

Institution: University of California, San Francisco
Investigator(s): Yang Xiao, Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12FT-0179 Award: $69,600
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
It has long been known that cigarette smoke can lead to lung damage that begins with an inflammation response and could eventually result in tumor formation. A key player in this process is thought to be Transforming Growth Factor a (TGF-a), a protein that can activate cell proliferation when binding to its receptor, EGFR (epidermal growth factor receptor). TGF-a and EGFR are required to promote lung cells to form tumors. Although both benign and tumorigenic human lung cells can produce TGF-a, the cells that are capable of forming tumors express increased amounts of TGF-a. In addition to its expression level, the activity of TGF-a is also regulated. One such activity modification is by protein cleavage that will release TGF-a from cell membrane to form a soluble protein. In soluble form TGF-a can act on neighboring (e.g. stromal) cells and also provide a positive proliferation feedback to the same cells where it was produced. Soluble TGF-a can also be internalized together with its receptor, EGFR, and this is associated with a poor prognostic outcome in patients. The key to cleavage of transmembrane TGF-a is a transmembrane metalloproteinase enzyme, called TACE. Induction of TACE phosphorylation by cigarette smoke correlates with induced TGF-a cleavage.

The aims of this proposal are to study the regulation of TACE-mediated TGF-a cleavage and its effects on cancer progression. We will investigate whether TACE is regulated from the inside of cancer cells via the Erk/MAPK pathways of signaling. We propose to identify the precise region of TACE that becomes phosphorylated, and determine whether there are existing or unknown proteins that interact to influence TACE activation. Lung cancer cells will also be treated with ectodomain cleavage blockers and monitored for their response to cigarette smoke by examining key cancer markers.

This study will not only expand our knowledge of the transition from normal epithelial to lung cancer cells, but also could identify new potential drug targets for cancer prevention and treatment.