Tumor suppressor p53 is the most frequently mutated gene in tumors. Many mutant p53 (mutp53) proteins promote tumorigenesis through the gain-of-function (GOF) mechanism. Mutp53 proteins often accumulate to high levels in tumors, which is critical for mutp53 GOF. Its underlying mechanism is poorly understood. Here, we found that BAG2, a protein of Bcl-2 associated athanogene (BAG) family, promotes mutp53 accumulation and GOF in tumors. Mechanistically, BAG2 binds to mutp53 and translocates to the nucleus to inhibit the MDM2-mutp53 interaction, and MDM2-mediated ubiquitination and degradation of mutp53. Thus, BAG2 promotes mutp53 accumulation and GOF in tumor growth, metastasis and chemoresistance. BAG2 is frequently overexpressed in tumors. BAG2 overexpression is associated with poor prognosis in patients and mutp53 accumulation in tumors. These findings revealed a novel and important mechanism for mutp53 accumulation and GOF in tumors, and also uncovered an important role of BAG2 in tumorigenesis through promoting mutp53 accumulation and GOF.
Cancer can develop if cells in the body acquire mutations that enable them to grow rapidly to form a mass called a tumor. The gene that encodes a protein called p53 is the most commonly mutated gene in human tumors. Most of these mutations result in the production of mutant p53 proteins that are similar in size to the normal protein, but do not work in the same way.
The normal p53 protein is known as a ‘tumor suppressor’ because it promotes the repair of damaged genetic material and stops the cell from dividing while this repair is underway. Also, it can instruct a cell to die if the damage is too great to repair. However, many of the mutant p53 proteins stop performing these roles and gain new activities that promote tumor growth instead. These activities often rely on the mutant p53 proteins accumulating to very high levels, but it is not clear why this happens.
Here, Yue, Zhao et al. used biochemical techniques to search for other proteins that can bind to mutant p53 proteins. The experiments reveal that a protein called BAG2 binds to mutant p53 and promotes its accumulation in cancer cells, which increases the activity of mutant p53 in driving tumor growth. Loss of BAG2 leads to a reduction in the level of mutant p53 in cells and inhibits the activity of mutant p53.
Using a public database of genetic data from human tumors, Yue, Zhao et al. found that human tumor cells often contain higher levels of BAG2 than normal cells. Furthermore, patients with tumors that had high levels of BAG2—and therefore accumulated mutant p53 proteins—were less likely to have positive outcomes after medical treatment.
Yue, Zhao et al.'s findings suggest that increased production of BAG2 in many tumors may be responsible for the accumulation of mutant p53 proteins that drive tumor growth. A future goal is to develop a new treatment strategy that targets BAG2 in tumors to prevent the accumulation of mutant p53 proteins and therefore block the growth of tumors.