apoptosis in cancer cells
Researchers say they have identified a new mechanism by which the tumor suppressor protein p53 triggers apoptosis, and they believe this process could be harnessed to kill cancer cells.
The team discovered how p53 acts in the cytoplasm to trigger cell death by binding to and activating the BAX protein.
The process involves a shape change in one of p53’s amino acids that serves as the “switch” to activate BAX and trigger the apoptotic pathway.
The team also identified the enzyme in the cytoplasm that promotes the change that controls the “switch.”
Richard Kriwacki, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described these findings in Molecular Cell.
Like up to half of all proteins, p53 includes both structured and disordered regions. A disordered region is a segment that does not adopt a single shape but
remains flexible and constantly switches between different shapes until
it encounters a partner.
Dr Kriwacki and his colleagues showed that both structured and disordered regions of p53 play a role in BAX activation in the cytoplasm.
The process starts when a structured region of p53 known as the DNA-binding domain binds to BAX. That sets the stage for the unstructured region of p53 to form a second bond, which activates BAX and triggers apoptosis.
“There were no previous reports of this disordered region of p53 binding to BAX, so the finding that this region was the key to BAX activation was a total surprise,” Dr Kriwacki said.
The disordered p53 segment included the amino acid proline, which can change between two shapes, particularly in the presence of the enzyme Pin1.
Using NMR spectroscopy, the researchers showed that the proline shape change promotes p53 binding and activation of BAX.
“These results expand our understanding of the different ways p53 modulates cell behavior,” Dr Kriwacki said. “The findings also raise the possibility of killing tumor cells using small molecules to trigger BAX-dependent apoptosis.”
