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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090885-02
Application #
6922061
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2004-07-15
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$204,525
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Gomez-Millan, Jaime; Goldblatt, Erin M; Gryaznov, Sergei M et al. (2007) Specific telomere dysfunction induced by GRN163L increases radiation sensitivity in breast cancer cells. Int J Radiat Oncol Biol Phys 67:897-905
Mendonca, Marc S; Mayhugh, Brendan M; McDowell, Berry et al. (2005) A radiation-induced acute apoptosis involving TP53 and BAX precedes the delayed apoptosis and neoplastic transformation of CGL1 human hybrid cells. Radiat Res 163:614-22
Tanaka, Hiromi; Mendonca, Marc S; Bradshaw, Paul S et al. (2005) DNA damage-induced phosphorylation of the human telomere-associated protein TRF2. Proc Natl Acad Sci U S A 102:15539-44