Mutations in tumor suppressor take other genes down with them

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p53 is a potent tumor suppressor. Its job is to scan along DNA, identify mutations that might cause cancer, and then halt cell growth until they can be repaired—it kills the cell if they cannot. It is mutated in approximately 50 percent of human tumors, and in its absence, DNA mutations can accrue while the cell divides, often forming a tumor. But some p53 mutants exhibit a nefarious “dominant negative” effect: when they are around, they prevent wild-type (normal) p53 molecules from working.

Because p53 works as a tetramer—a complex of four p53 molecules all bound together—it has generally been presumed that this dominant negative effect is achieved when mutant p53 molecules link up with normal counterparts to form nonfunctional tetramers. But new work reported in Nature Chemical Biology suggests that the process is more complex; some mutants can form much larger aggregates, not only with wild-type p53 but also with its related tumor suppressors p63 and p73. In addition to its blocking the function of these proteins, this aggregation can induce cellular changes that further contribute to tumorigenesis.

Most cancer-causing mutations in p53 are in the sequences that enable it to bind DNA, but scientists in Joost Schymkowitz’s lab in Belgium found that some mutations were clustered in another part of the protein. In cancer cells, p53 molecules with these mutations were seen bunched up in large complexes in the cytoplasm, rather than in the nucleus, where the DNA is.

The mutations turned out to be in a hydrophobic stretch of amino acids that is generally buried inside the molecule, as is the preference of hydrophobic things in water. These mutations disrupted p53’s structure, exposing this hydrophobic region to the aqueous intracellular milieu. The aggregation occurs when these exposed hydrophobic amino acids glom together in an attempt to get covered back up.

The researchers next looked at the relative importance of aggregation and forming ineffective tetramers by making mutants in the tetramerization domain and the aggregation domain. Mutants that caused aggregation still exerted dominant negative activity, even when they could no longer form tetramers and they could still form complexes with wild-type p53 molecules. p53 molecules with mutations in the tetramerization domain, in contrast, did not form complexes with wild-type p53.

Mutations in a tumor suppressor gene like p53 often lead to tumor formation via Loss of Heterozygosity (LOH). If a cell has a mutation in one of its p53 genes, it's not such a big deal, because the cell is heterozygous—it still has a wild-type p53 gene on the chromosome from the other parent. But if the second copy of the gene gets mutated as well and heterozygosity is lost, a tumor can start to develop.

These scientists found that p53 mutations that cause aggregation have a lower rate of LOH than mutants in the DNA binding region. This is exactly what should happen if these mutations are exerting a strong dominant negative effect, because then LOH becomes unnecessary; the same effect is achieved because the mutant inactivates any wild-type molecules. Breast and colon cancer patients with aggregating mutants also had a poorer prognosis than those with other p53 mutations.

This idea explains the well-known but poorly understood observation that mutant p53 can inactivate p63 and p73, even though p53 cannot form tetramers with these molecules. The authors suggest that the different rates and amounts of protein aggregation might explain the variability in different tumor cells.

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