Numerous changes occur in the cAMP second messenger pathway in lung epithelial tumors and neoplastic lung cell lines. This is important because cAMP analogs inhibit urethan induction of lung tumorigenesis but accelerate the growth rate of initiated tumors. These bidirectional effects of cAMP may be a function of the altered content and properties of the cAMP-dependent protein kinase (PKA) in lung tumors. Whether cAMP inhibits initiation or clonal expansion of initiated cells will now be determined, as will identification of the PKA isozyme mediating cAMP modulation by using isozyme-specific cAMP analogs, effects of cAMP on proliferation of lung epithelia in vivo and lung cells in vitro will be examined, and whether strain differences between proliferative rates of lung epithelia in vivo correlate with susceptibility to tumorigenesis or to the histogenic precursors of lung tumors in studies using recombinant inbred strains of mice. The mechanisms underlying the neoplastic changes in PKA will be examined in transfection studies of immortalized lung cell lines with the K-ras transforming oncogene, by determining whether PKA content and properties are altered after down-regulating protein kinase C and after varying serum concentrations, determining if the regulatory subunit of PKA isozyme II binds different protein substrates in the tumor, examining PKA alterations in Clara cells isolated from mice treated with cAMP analogs or with urethan, and determining the PKA isozyme specificity for the reciprocal effects on endogenous protein phosphorylation caused by cAMP in normal neoplastic lung cells. Understanding the roles of PKA in neoplastic progression will be useful in future studies of lung cancer prevention, diagnosis and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002370-12
Application #
3249737
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1980-04-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
12
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Type
Schools of Pharmacy
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
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