There are processes in the human body that can suppress the growth and spread of cancer cells. These mechanisms, including those involving the tumor suppressor protein p53, are extensively studied due to their critical role in disease. Through studies of proteins that regulate p53, scientists at St. Jude Children’s Research Hospital have uncovered a previously unknown tumor suppression mechanism. The p14 Alternative Reading Frame protein (p14 ARF), normally present in low amounts in cells, is expressed in higher amounts under oncogenic stress and activates p53. The researchers identified an alternative tumor suppression mechanism for p14 ARF and demonstrated how condensate formation and disruptions in ribosome production contribute to this process. The findings were published today in Nature Communications.
The researchers showed that increased expression of p14 ARF causes phase separation of the protein from other cellular components. This occurs in the nucleolus, a membrane-less compartment within the cell nucleus responsible for ribosome production. In the nucleolus, p14 ARF binds to nucleophosmin, a protein essential for ribosome production, and phase separates from it. This creates a gel-like state that leads to decreased nucleophosmin dynamics, stalled ribosome biogenesis, and cell toxicity. The process initiated by p14 ARF thus represents a likely alternative pathway for tumor suppression.
p14 ARF blocks work in the nucleolus
"p14 ARF is normally expressed at very low levels in healthy cells, but increased expression is induced in response to oncogenic stress, such as upregulation of MYC or other oncogenes," explains corresponding author Richard Kriwacki, PhD, Department of Structural Biology at St. Jude University.
https://www.nature.com/articles/s41467-024-53904-z
