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Role of protein phosphatase 2A in lung cancer

Institution: University of California, San Diego
Investigator(s): Gernot Walter, Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11RT-0022 Award: $405,795
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Smoking causes lung cancer through mutation of genes that are involved in controlling the growth of lung cells. Two classes of genes are important in growth control: (1) Genes that stimulate growth (oncogenes), and (2) genes that inhibit growth (tumor suppressor genes). The former become activated by mutation whereas the latter become inactivated by mutation or deletion. In most cancers, including lung cancer, mutation of both types of genes contributes to the development of cancer.

For many years, our laboratory has investigated the enzyme called protein phosphatase 2A (PP2A). PP2A controls the function of other proteins by removing phosphate residues from the amino acids serine and threonine. PP2A consists of a trimeric complex of a catalytic subunit (C) and two regulatory subunits (A and B). There are two different forms of A (Aa and Ab), two forms of C (Ca and Cb), and many different forms of B subunits grouped in families called B, B', B'', and B'''. Both forms of A were recently found to be mutated or deleted in lung cancer and other cancers, suggesting that they play a role as tumor suppressors. Our previous hypothesis was that these mutations affect the capacity of the A subunits to bind certain B subunits and thereby inhibit formation of specific trimeric PP2A complexes that are important in tumor suppression. During the previous funding period we have demonstrated that this hypothesis is indeed correct. Some mutations are highly specific causing the A subunit to be defective in B' binding only, while being normal in B and B'' binding. Now, we propose that expression of A subunit mutants defective in binding B' subunits triggers a signal in the cytoplasm that is transmitted to the cell nucleus and stimulates cell growth. The particular pathway that we believe to be triggered by mutation is called the Wnt signaling pathway.

The proposed work is highly relevant to understanding the cause of lung cancer since it is expected to establish a link between A subunit mutations that occur in lung cancer and the Wnt signaling pathway which plays an important role in many cancers. Several A subunit mutants were found in tumor cell lines from smokers, suggesting that smoking may result in a loss of the tumor suppressor function of PP2A. It is conceivable that in the future, based on our studies, drugs can be found that revert the effect of A subunit mutations in lung cancer, i.e. drugs that bind to a mutant A subunit and restore its binding to the B' subunit resulting in normal function of PP2A. Since we are dealing with an enzyme, searching for such drugs in a natural product or synthetic compound library is a realistic future goal.
Publications

Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A: differences in expression, subunit interaction, and evolution.
Periodical: Biochemical Journal Index Medicus:
Authors: Zhou J, Pham H, Ruidiger R, Walter G ART
Yr: 2003 Vol: 369 Nbr: Abs: Pg: 387-398

The formation and activity of PP2A holoenzymes do not depend on the isoform of the catalytic subunit.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Zhou J, Pham H, Walter G ART
Yr: 2003 Vol: 278 Nbr: Abs: Pg: 8617-8622