Role of protein phosphatase 2A in lung cancer
Initial Award Abstract
Twenty years ago, PP2A was considered a nonspecific phosphatase. Since then, it turned into one of the most sophisticated and fascinating proteins, which is highly regulated by a large number of subunits, and implicated in numerous regulatory processes. Based on early studies, it has been suggested that PP2A is a tumor suppressor, and recent observations from our laboratory and others lent further support to this notion. But proof is still missing. The present proposal is an attempt to provide a definitive answer to the question of whether PP2A is a tumor suppressor in lung epithelium of mice.
PP2A holoenzymes are composed of one catalytic C subunit (C or C), one regulatory/scaffolding A subunit (A or A), and one regulatory B subunit (B, B', or B''). Recently, the genes encoding A and A were found to be mutated in a significant number of human carcinomas including lung carcinomas. Importantly, we found that all cancer-associated A and most A mutations encode proteins defective in binding B or both B and C subunits. We proposed that mutations in A or A, which impair binding of B or B and C subunits, destroy the tumor suppressor activity of PP2A, thereby promoting cancer development. To obtain direct evidence for this hypothesis, we plan to generate mice expressing the A mutation E64D (glutamic acid at position 64 replaced by aspartic acid) in adult lung epithelium. E64D was discovered in a lung carcinoma and is specifically defective in binding B' subunits but normal in binding C, C, B and B'' subunits. If E64D promotes tumor formation in the lung of mice, it very likely plays a similar role in humans.
Mutations of the A and A genes in human carcinomas are relatively frequent. Furthermore, A expression is shut down in 43% of glioblastomas. Therefore, PP2A might be a major player in human cancer development. It could also become a target for anti-cancer drugs designed to rescue the damage caused by mutation. Since PP2A is an enzyme, the search for drugs would be a realistic goal in the future. |