Researchers at the Keck School of Medicine of USC have discovered that only a small region of a protein responsible for controlling the proliferation of both normal and cancer cells is required for the initial process of turning on genes.
The findings hold promise for the eventual development of a molecular inhibitor that would target the area researchers identified and prevent cancer genes from being activated.
The study, “Functional Analysis of E2F1 Genomic Recruitment,” appeared in the April 8 issue of The Journal of Biological Chemistry.
Keck School professor Peggy Farnham, holder of the William M. Keck Endowed Chair in Biochemistry at USC Norris Comprehensive Cancer Center and Hospital, was the lead investigator for the study. A significant portion of the research was conducted by Alina R. Cao, a graduate student in Farnham’s laboratory, as part of her dissertation.
The protein investigated was E2F1, a transcription factor, or protein that binds to specific DNA sequences and controls the flow (or transcription) of genetic information by reading and interpreting the genetic “blueprint” in the DNA. Groupings of these type of proteins control when genes are switched on or off.
“Our previous studies showed that the E2F1 protein is precisely located at the start of transcription of thousands of human genes,” Farnham said. “Just knowing that it’s turning on a huge percentage of genes in the human genome was pretty surprising.”
In the most recent study, the Farnham lab sought to discover which part of that protein was involved in binding to the DNA.
“Using a series of mutant E2F1 proteins, we analyzed their binding throughout the genome of human breast cancer cells, testing the hypothesis that protein-protein interactions are involved in recruiting E2F1 to the genes that it controls,” she said. “Surprisingly, we found no evidence of that. Rather only the small area of E2F1 that interacts with DNA is involved.”
Farnham explained that changes in the way genes are expressed long have been linked to a variety of human diseases, including cancers and developmental disorders. As a result, many scientists are seeking to expand their understanding of how the process of transcription contributes to gene regulation. Sequencing of the human genome and recent technological advances in genome analysis have provided new approaches to pursue this goal.
“Our hope is that in the future we could design small-molecule inhibitors to disrupt the binding of E2F1 to promoters [the DNA at the beginning of genes that promotes expression], getting it to lift off of the DNA in cancer cells,” Farnham said. “In this way, we would be able to stop or slow the growth of cancer.”