Transcription factors are genes that, once expressed, can influence the activity of other genes, sometimes many other genes. There are hundreds of transcription factors in human cells that we know of, and they can bind to other parts of the genome. Some transcription factors (TFs) perform essential functions and influence many aspects of biology. Scientists have now developed a new way to inhibit transcription factors. This work, published in Cell Reports, could help scientists create new disease treatment approaches.
"This class of proteins represents one of the most high-impact therapeutic targets in biomedicine," said senior study author Professor Dylan Taatjes of CU Bolder. "We provide a completely new strategy for blocking transcription factor function that could have broad applications to many diseases, including and beyond cancer."
TFs are at work in many different types of cells, and in a variety of processes. When there are mutations in a TF, there may be many different downstream impacts as the expression of many other genes is altered. Proteins that should be helpful to the cell, and might tamp down inflammation or control cell division, can become harmful, "like Jekyll and Hyde," said Taatjes.
In this study, the researchers focused on a crucial transcription factor called p53, which plays a role in the cell cycle. When p53 functions normally, it stops the growth of tumors. But mutations in p53 can turn it into a tumor promoter.
Targeting transcription factors, including p53, has been challenging for researchers, in part because many are similar and difficult to interfere with in a specific way. As such, disrupting one TF can lead to a wide range of cellular effects, many of which may be unintended.
"Unfortunately, despite the huge potential and years of effort, therapeutic targeting of transcription factors has proven largely intractable," Taatjes said.
Taatjes and colleagues have been working on this problem for years. They wanted to target p53, a master regulator in every type of cell that' has a known role in some kinds of cancer.
But they did not aim directly at the p53 transcription factor; they directed their attention to a complex called Mediator. While it's not well-understood, Mediator is known to be essential for some TFs. Without Mediator, some TFs cannot trigger transcription. The team developed a peptide that blocked the link between p53 and Mediator, which specifically halted transcription that would have been triggered by p53 in human cells.
"Here we have found a way to get the functional equivalent without actually targeting the transcription factor but Mediator instead," said Taatjes. "And, importantly, this does not negatively affect other transcription factors in the cell."
More research will be needed before this research can be used as a therapeutic strategy. However, it may also open new avenues for treating other disorders that are caused by mutated TFs.
"The methods we discuss here could potentially apply to any disease that is driven by aberrant transcription factor function," Taatjes said.