NMR reveals cancer clue: p53 activity

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  • Published: Aug 15, 2015
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: NMR reveals cancer clue: p53 activity

Programming skills

Richard Kriwacki member of St. Jude faculty (left), explains research and data to Ariele Follis a postdoctoral research associate at St. Jude (Credit: St. Jude Children's Research Hospital/Peter Barta)

US researchers have used NMR spectroscopy in a study of the activity of the tumour suppressor protein, p53. Their work reveals the mechanism by which p53 triggers programmed cell death (apoptosis) and may have implications for understanding the development of various forms of cancer and perhaps lead to new drug discoveries.

p53 is well known for its role in cancer prevention in the body. The protein, or more precisely, the pathway that controls p53's function, is inactivated in most cancers. But, in healthy cells p53 works in the cell nucleus as a transcription factor, regulating apoptosis by controlling expression of specific genes, including those involved in the process of programmed cell death itself.

Apposite apoptosis

Previous work by researchers at St Jude Children's Research Hospital in Memphis, Tennessee, and others demonstrated how p53 works in the cell's cytoplasm to initiate apoptosis by first binding to and thus activating a protein called BAX. Now, the St Jude's team has finally pinned down the mechanism. They have demonstrated that this activation process involves a change in one of the amino acids in p53 to act as a biochemical "switch". The team has also found the enzyme that promotes that amino acid change and so flips the switch.

"These results expand our understanding of the different ways p53 modulates cell behaviour. The findings also raise the possibility of killing tumour cells using small molecules to trigger BAX-dependent apoptosis," explains structural biologist Richard Kriwacki. The latest development is the culmination of more than ten years work by Green and Kriwacki and their respective laboratories into the activity of p53 acts in the cytoplasm and its ability to modulate apoptosis.

Universality

"The p53 protein is almost universally regarded as working in the nucleus and was thought to have no function in other parts of the cell," Green adds. "Our study provides the first biophysical insights into how p53 can have another function, one with important consequences for cancer."

The p53 protein is not unlike about half of all proteins, in that it has both structured and flexible, disordered regions and for p53 this characteristic is critical, on both counts, for BAX activation in the cytoplasm. The process starts when a structured region of p53 region known as the DNA-binding domain first binds to BAX. This establishes the appropriate environment for the unstructured region of p53 to make an additional bond with BAX to activate it. "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," Kriwacki explains. The team demonstrated that it is the proline amino acid in the disordered p53 segment that allows it to toggle between two shapes, when in the presence of the enzyme Pin1. The NMR data prove that the changing proline promotes the p53 binding and activation of BAX.

Ultimately, such work will help in drug discovery, perhaps leading to molecules that reactivate or mimic the shape "switch" and so trigger apoptosis in tumour cells where the process of programmed cell death is failing leading to the characteristic runaway cell replication of cancer. "That is a future direction of this research," Kriwacki adds.

Related Links

Molec Cell 2015, in press: "Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis."

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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