Molecular events in the induction of murine tumors by ionizing radiation.
AuthorAndrews, Kaya Lynn.
Committee ChairBowden, G. Timothy
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractA new method is presented to identify and clone novel transforming genes from radiation-induced tumors. This method involves the creation of a cDNA expression library from radiation-induced tumors. The library is transfected into non-transformed cells, and the nude mouse tumorigenicity assay functionally defines the acquisition of a transformed phenotype. cDNA clones responsible for transformation are rescued by PCR amplification. This method is applicable to a variety of mammalian systems. The only requirement is a functional assay with which to measure the acquisition of an altered phenotype following transfection of a cDNA library. While this method has not yet been applied to a radiation-induced tumor, it has identified a cDNA for the 16 kD subunit of v-H⁺-ATPase, which has been associated with cellular transformation. Two protocols were used to generate radiation-induced tumors. One experiment utilizing fractionated doses of ionizing radiation had a much greater tumor yield than the second protocol using a single dose of 11.25 Gy. To determine if the mechanism of gene activation is different in radiation- and chemically-induced tumors, the expression pattern of five tumor-associated genes was analyzed. The expression patterns of mals 1-4 were not significantly different in tumors generated by the two carcinogens. However, transin, a secreted protease, was overexpressed in radiation-induced papillomas and undetectable in chemically-induced papillomas. This observation supports previous studies indicating a higher conversion rate of radiation-initiated benign papillomas to malignant squamous cell carcinomas when compared to their chemically-initiated counterparts. Transin degrades basement membrane proteins and may be involved in the progression of benign, encapsulated tumors to malignant, invasive squamous cell carcinomas. Isolation and characterization of genes with dominant transforming activity from radiation-induced tumors will provide information to bridge the gap between the initial ionizing radiation event and the subsequent development of malignant tumors. The function of these genes may also provide information about the development of human malignancies. An understanding the natural biology of cells will help elucidate the pathogenesis cancer and other diseases.
Degree ProgramMicrobiology and Immunology