Regulation of BCL-2 and Tumorigenicity

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

DESCRIPTION (provided by applicant): A better understanding of the molecular basis of radiation-induced carcinogenesis will give us insight into radiation-induced secondary malignancies and new strategies to prevent them. Radiation-induced neoplastic transformation of human CGL1 cells involves loss of novel tumor suppressor locus on chromosomes 11. Our analysis of radiation-induced neoplastically transformed cell lines called GIMs has now narrowed the location of the tumor suppressor gene to a 30 kb interval on chromosome 11 and identified PACS1 and nearby FRA1 as candidate tumor suppressor genes. We have also found that the majority of the GIMs highly over express the anti-apoptotic Bcl-2. In Specific Aim 1, we will identify the tumor suppressor gene(s) on chromosome 11 involved in radiation-induced carcinogenesis. Based on our preliminary data, the working hypothesis is that PACS1 and/or FRA1 are candidate tumor suppressor genes on chromosome 11. We will test whether exogenous re-expression of PACS1 and/or FRA1 in the radiation-induced neoplastically transformed GIMs will suppress or inhibit tumor growth in nude mice. Conversely, we will also test whether inhibition of PACS1 and/or FRA1 expression in CGL1 cells causes induces tumorigenicity. Alternative candidate genes adjacent to the HeLa/cervical cancer tumor suppressor locus will be investigated if required. In Specific Aim 2, we will determine the genes that are regulated by or interact with the identified tumor suppressor gene(s) and their role in the radiation-induced carcinogenesis. Based on our preliminary data, our working hypothesis is that radiation-induced neoplastic transformation leads to loss of BCL-2 transcriptional regulation, over expression of Bcl-2 protein, apoptotic deregulation, and tumor formation in nude mice. We will therefore identify the negative transcriptional regulator(s) of the BCL-2 gene in CGL1 cells and normal cervical epithelial cells and investigate whether the identified tumor suppressor gene from Specific Aim l are involved in BCL-2 regulation. The overall hypothesis to be tested here is that radiation-induced neoplastic transformation is caused by the loss of the candidate tumor suppressor gene on chromosome 11 that leads to over expression of BCL-2, apoptotic deregulation, and tumorigenicity in this premalignant cancer model.