Role of protein phosphatase 2A in lung cancer
Abstracts
Initial Award Abstract |
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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 (Ca or Cb), one regulatory/scaffolding A subunit (Aa or Ab), and one regulatory B subunit (B, B', or B''). Recently, the genes encoding Aa and Ab were found to be mutated in a significant number of human carcinomas including lung carcinomas. Importantly, we found that all cancer-associated Aa and most Ab mutations encode proteins defective in binding B or both B and C subunits. We proposed that mutations in Aa or Ab, 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 Aa 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 Ca, Cb, 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 Aa and Ab genes in human carcinomas are relatively frequent. Furthermore, Aa 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. |
