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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: 1999 (Cycle 8) Grant #: 8RT-0037 Award: $307,522
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. 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 a type of protein that facilitates metabolic processes, i.e., an enzyme. In particular, we are interested in the enzyme known as protein phosphatase 2A (PP2A). PP2A controls the function of other proteins by removing phosphate residues from the amino acids serine and threonine. PP2A is composed of three different protein components (or subunits) that are called A, B, and C. One form of A subunit, called Awas recently found to be mutated or deleted in lung and colon cancer cells, suggesting that Aplays a role as tumor suppressor in lung and colon cancer. Our hypothesis is that mutations in the Asubunit destroy its tumor suppressing activity of protein phosphatase 2A by abolishing the interaction between Aand the other two subunits B and C. To test this hypothesis, we will carry out binding experiments with normal and mutated A, B, and C subunits using assays that were previously developed in our laboratory.

Our work is relevant to lung cancer, in particular since it is highly likely that smoking causes mutations in the A subunit resulting in loss of the tumor suppressing function of PP2A. It is conceivable that, based on our proposed studies, drugs can be found that revert the effect of A mutations in lung and colon cancer; i.e., drugs that bind to A mutant-containing core enzyme and exert the same effect on enzyme activity as the tumor suppressing B subunit. Since we are dealing with an enzyme, searching for drugs in a natural product or synthetic compound library is a worthwhile and realistic goal.

Final Report
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 (A and A), two forms of C (C and C), 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 three-year TRDRP funding period we have demonstrated that this hypothesis is indeed correct. Some mutations are highly specific causing the A subunits to be defective in B' binding only, while being normal in B and B'' binding. Similar results were found for the A subunit mutants.

For the future, we propose that expression of A subunit mutants in cancer, which are 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 might be triggered by mutation is called Wnt signaling pathway.

Our findings and the resulting future work are highly relevant to understanding the cause of lung cancer since they are 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.
Publications

Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Abeta subunit gene
Periodical: Oncogene Index Medicus:
Authors: Ruediger R, Pham HT, Walter G ART
Yr: 2001 Vol: 20 Nbr: Abs: Pg: 1892-1899

Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the Aalpha subunit gene
Periodical: Oncogene Index Medicus:
Authors: Ruediger R, Pham HT, Walter GF ART
Yr: 2001 Vol: 20 Nbr: Abs: Pg: 10-15

Reduced expression of the A-alpha subunit of protein phosphate 2A in human gilomas in the absence of mutations in the A-alpha and A-beta subunit genes
Periodical: International Journal of Cancer Index Medicus:
Authors: Colella S, Ohgaki H, Ruediger R, et al ART
Yr: 2001 Vol: 93 Nbr: Abs: Pg: 798 - 804