Research Methods for Occupational Cancer are needed to develop early markers of adverse health effects from workplace exposures and to devise ways for interrupting the pathways between workplace exposures and resultant cancers. The p53 tumor suppressor gene product is a potential target for both of these approaches. Certain occupational exposures can produce mutations in p53 which cause the generation of an immune response with circulating p53 auto-antibodies, even before the occurrence of clinically detectable cancers, so that these antibodies may serve as useful early markers of adverse effects. In addition, certain short peptide sequences from p53 have been demonstrated in cell culture to be able to cause mutant p53 to revert to normal function, resulting in the death of cancer cells containing mutant p53 but with no effect on normal cells with wild-type p53, suggesting that this may be a useful approach for interrupting the pathway between workplace exposures that produce p53 mutations and resultant cancers. The purpose of the proposed research is to examine both of these approaches for occupational cancers caused by asbestos exposure in two related projects. For the first project, banked serum samples from a cohort of workers with asbestosis will be examined for the presence of p53 auto-antibodies by enzyme-linked immunosorbent assay and ininiunoblotting to determine if the presence of the antibodies correlates with the subsequent development of cancer, as well as with the presence of p53 mutations in the resultant tumors. For the second project, the effects in cell culture of a p53 peptide sequence (delivered as the peptide or as a plasmid-based mini-gene) on asbestos-associated lung cancer and mesothelioma cell lines with and without p53 mutations and corresponding non-cancer cell lines with wild-type p53 will be investigated, as well as determining the mechanism of action of the peptide for inducing death in these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute for Occupational Safety and Health (NIOSH)
Type
Research Project (R01)
Project #
5R01OH007590-03
Application #
6753496
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Newhall, Jim
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$209,280
Indirect Cost
Name
Columbia University (N.Y.)
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Tooker, Brian C; Newman, Lee S; Bowler, Russell P et al. (2011) Proteomic detection of cancer in asbestosis patients using SELDI-TOF discovered serum protein biomarkers. Biomarkers 16:181-91
Li, Yongliang; Karjalainen, Antti; Koskinen, Heikki et al. (2009) Serum growth factors in asbestosis patients. Biomarkers 14:61-6
Li, Y; Chen, Y; Slavkovic, V et al. (2007) Serum levels of the extracellular domain of the epidermal growth factor receptor in individuals exposed to arsenic in drinking water in Bangladesh. Biomarkers 12:256-65
Senatus, Patrick B; Li, Yin; Mandigo, Christopher et al. (2006) Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide. Mol Cancer Ther 5:20-8
Li, Yongliang; Karjalainen, Antti; Koskinen, Heikki et al. (2005) p53 autoantibodies predict subsequent development of cancer. Int J Cancer 114:157-60
Li, Yin; Mao, Yuehua; Rosal, Ramon V et al. (2005) Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells. Int J Cancer 115:55-64
Li, Yin; Mao, Yuehua; Brandt-Rauf, Paul W et al. (2005) Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. Mol Cancer Ther 4:901-9
Rosal, Ramon; Brandt-Rauf, Paul; Pincus, Matthew R et al. (2005) The role of alpha-helical structure in p53 peptides as a determinant for their mechanism of cell death: necrosis versus apoptosis. Adv Drug Deliv Rev 57:653-60
Rosal, Ramon; Pincus, Matthew R; Brandt-Rauf, Paul W et al. (2004) NMR solution structure of a peptide from the mdm-2 binding domain of the p53 protein that is selectively cytotoxic to cancer cells. Biochemistry 43:1854-61
Li, Yin; Rosal, Ramon V; Brandt-Rauf, Paul W et al. (2002) Correlation between hydrophobic properties and efficiency of carrier-mediated membrane transduction and apoptosis of a p53 C-terminal peptide. Biochem Biophys Res Commun 298:439-49