Interests:
Mouse models of lung disease, control of cell growth, transcriptional regulation.

a. p53 expression and lung fibrosis. Our laboratory has demonstrated expression of the p53 tumor suppressor protein at sites of fibrotic lesions after inhalation exposure of rodents to asbestos. To characterize p53 function in this rodent model of asbestos-induced pulmonary fibrosis, we prepared transgenic mice that express a dominant negative mutant form of p53 from the surfactant protein C promoter (SPC-DNp53 mice). These animals with inhibited p53 function in the lung epithelium appear to display reduced fibrogenesis post-exposure to asbestos. We postulate that p53-mediated apoptosis in asbestos-exposed mice contributes to injury of the lung epithelium, which can be ameliorated by inhibition of p53 function in these cells. In contrast to these results, exposure of the SPC-DNp53 mice to bleomycin by intratracheal instillation produces more pronounced fibrogenesis than that in simultaneously exposed nontransgenic littermates. We suggest that p53-mediated activation of DNA repair protects the lung epithelium from the extensive DNA damage induced by bleomycin.
b. p53 and malignant conversion. A strong correlation exists between mutations in the p53 gene and malignant conversion. The phenotypic alterations of the SPC-DNp53 mice described above are consistent with disrupted p53 function in the epithelial cells of the airways and the peripheral lung. This animal model is being used to study lung carcinogenesis induced by inhaled agents linked to human lung cancer to model the human disease in mice.
c. p53 mediated regulation of PCNA expression. One of the p53 target genes, proliferating cell nuclear antigen, PCNA, encodes a protein that functions in both DNA replication and repair. Accordingly, PCNA is expressed in cells exposed to mitogens or genotoxic stress. A body of evidence indicates that p53 can activate or repress

• Shan, B., Xu, J., Zhuo, Y., Morris, C.A. and Morris, G.F. Recruitment of the p300/CBP transcriptional co-activator and localized acetylation of histone H4 upon p53-dependent activation of the PCNA gene in irradiated human fibroblasts. (manuscript submitted).
  
  
• Shan, B. and Morris, G.F. Binding sequence-dependent regulation of the human proliferating cell nuclear antigen promoter by p53. (manuscript submitted).
  
  
• Ghosh, S., Mendoza, T., Ortiz, L.A., Hoyle, G.W., Fermin, C.D., Brody, A.R., Friedman, M. and Morris, G.F. Enhanced bleomycin sensitivity in mice expressing dominant negative p53 from the surfactant protein C promoter. American Journal of Respiratory and Critical Care Medicine 166: 890-897 (2002).
  
  
• Nelson A., Mendoza T., Hoyle G.W., Brody A.R., Fermin C. and Morris G.F. Enhancement of fibrogenesis by the p53 tumor supressor protein in asbestos-exposed rodents. Chest 120: 33S-34S (2001).
  
  
• Xu, J. and Morris, G.F. p53-mediated regulation of proliferating cell nuclear antigen (PCNA) expression in cells exposed to ionizing radiation. Molecular and Cellular Biology 19: 12-20 (1999).
  
  
• Morris, G.F. and Brody, A.R. Molecular mechanisms of particle-induced lung disease. pages 305-333. In: Environmental and Occupational Medicine. Rom, W.R. Ed. Little, Brown and Company, Boston, MA. (1998).