Anti-cancer protein turns cell nucleus into gel

The gel-like network of ARF protein traps another protein within itself, making it very difficult for the cell to divide.

Cells have mechanisms that prevent them from becoming cancerous, and perhaps the best known of these mechanisms involves the p53 protein. When too many defects accumulate in the genome, p53 inhibits cell division and turns on apoptosis, a program of cellular self-destruction; Thanks to apoptosis, the cell dies in a timely manner, without having time to cause trouble to anyone. But p53 is not alone. University of Tennessee staff and Children’s Hospital of St. Judas studied the work of another anti-cancer protein called p14^ARFor simply ARF. It is known that it stimulates the synthesis of p53, but it has now become clear that ARF is able to inhibit cancer, so to speak, on its own.

There is usually little ARF in the cell; its level jumps when there is a threat of malignant degeneration – for example, when the activity of oncogene proteins increases. In an article in Nature Communications it is said that ARF not only becomes abundant – it accumulates in the nucleus, more precisely, in the nucleolus. The nucleolus is the area where the assembly of ribosomes, protein-synthesizing molecular machines consisting of ribosomal RNA and ribosomal proteins, occurs. Protein synthesis occurs in the cytoplasm, but the assembly of ribosomes occurs in the nucleolus: the genes for ribosomal RNAs are assembled here, the synthesis of these RNAs occurs here, and here ribosomal proteins that came here from the cytoplasm sit on them. The nucleoli are not bounded by a membrane, but they are still considered a special cellular organelle; there may be one or two of them in one core.

Ribosome assembly involves various helpers, one of which is the protein nucleophosmin. Some of its main functions are related to ribosomal RNA: after synthesis, it helps them to properly prepare for the assembly of ribosomes, and then works as a chaperone, that is, it maintains RNA and proteins in the form that is needed for them to connect correctly with each other, preventing them from randomly clump together into useless molecular clumps. It is with this nucleophosmin that ARF interacts, but not just interacts, but forms a molecular condensate. (Recently, such molecular condensates have received increasing attention precisely because of their ability to influence various cellular processes, and also because methods have emerged that allow them to be observed and studied.)

Having accumulated in the nucleolus, ARF enters a gel-like state, and this ARF gel absorbs nucleophosmin. A phase separation occurs, similar to what we see in the case of oil and water: lipid molecules cannot leave the oil droplet into the water, water cannot enter the oil droplet. When ARF becomes a gel, it changes its spatial structure, so that the gel looks like a network of molecules that hold each other quite tightly. They are held together by their hydrophobic regions, so the analogy with oil and water is partly correct. It is difficult for nucleophosmin to leave this network, so the nucleolus is deprived of one of the main assistants in the assembly of ribosomes. As a result, there are few ribosomes, protein synthesis slows down, and the cell, even if it is a hundred times malignant, stops dividing.

It has long been known that mutations in ARF are associated with cancer, but now it is possible to better understand how exactly ARF prevents such diseases from developing. It is possible that new information about it will be useful in the clinic – for example, one can imagine a drug that stimulates the work of ARF in malignant cells, suppressing protein synthesis in them.