Autoregulation of Protein Phosphatase Type 2A Expression (1998)

Protein phosphatases are involved in many cellular processes. One of the most abundant of these enzymes, the serine/threonine-specific protein phosphatase type 2A (PP2A), is present in most eukaryotic cells and serves a variety of functions. However, the detailed study of its regulation and function has been hampered by the difficulty of manipulating its expression level in cell culture. By using a new mammalian expression vector to forcibly overexpress PP2A in the mouse fibroblast cell line NIH3T3, we now show that the catalytic subunit of PP2A is subject to a potent autoregulatory mechanism that adjusts PP2A protein to constant levels. This control is exerted at the translational level and does not involve regulation of transcription or RNA processing. Thus, our results demonstrate tight control of PP2A expression, and provide an explanation for the difficulty of increasing PP2A expression experimentally. Protein phosphatases are involved in many cellular processes. One of the most abundant of these enzymes, the serine/threonine-specific protein phosphatase type 2A (PP2A), is present in most eukaryotic cells and serves a variety of functions. However, the detailed study of its regulation and function has been hampered by the difficulty of manipulating its expression level in cell culture. By using a new mammalian expression vector to forcibly overexpress PP2A in the mouse fibroblast cell line NIH3T3, we now show that the catalytic subunit of PP2A is subject to a potent autoregulatory mechanism that adjusts PP2A protein to constant levels. This control is exerted at the translational level and does not involve regulation of transcription or RNA processing. Thus, our results demonstrate tight control of PP2A expression, and provide an explanation for the difficulty of increasing PP2A expression experimentally. Reversible protein phosphorylation events play a key role in many cellular processes, such as metabolic pathways, ion channel regulation, signal transduction pathways, and the regulation of gene expression. While one component of this regulation, the protein kinases, has been studied intensively, the importance of the other component, the protein phosphatases, has only lately received more acknowledgment. The finding that some phosphatases are crucial components of pathways that regulate cellular growth and, consequently, may play a role in the process of tumorigenic transformation, has brought them to the forefront of cancer research (1Lee T.H. Semin. Cancer Biol. 1995; 6: 203-209Crossref PubMed Scopus (32) Google Scholar, 2Wera S. Hemmings B.A. Biochem. J. 1995; 311: 17-29Crossref PubMed Scopus (597) Google Scholar, 3Schönthal A.H. Semin. Cancer Biol. 1995; 6: 239-248Crossref PubMed Scopus (35) Google Scholar, 4Mumby M.C. Walter PubMed Scopus Google Scholar, S. Semin. 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PubMed Scopus Google Scholar, Walter Biol. PubMed Scopus Google the of PP2A the of in mammalian cells Cancer Google Scholar, Biochem. PubMed Scopus Google S. Biochem. PubMed Scopus Google by of constant of PP2A protein in a in PP2A and constant protein by our finding of a potent autoregulatory mechanism of PP2A protein PP2A protein are of of PP2A (1Lee T.H. Semin. Cancer Biol. 1995; 6: 203-209Crossref PubMed Scopus (32) Google Scholar, 4Mumby M.C. Walter PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar, Walter M.C. Biol. PubMed Scopus Google of PP2A brought by by such as the S. J. Biol. PubMed Scopus Google Scholar, S. J. Biol. PubMed Scopus Google or protein 1995; PubMed Scopus Google PP2A has been to other cellular its phosphatase PubMed Scopus Google Scholar, PubMed Scopus Google of the catalytic subunit been in the regulation of PP2A Hemmings B.A. J. Biol. 1995; PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar, J. 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The finding that some phosphatases are crucial components of pathways that regulate cellular growth and, consequently, may play a role in the process of tumorigenic transformation, has brought them to the forefront of cancer research (1Lee T.H. Semin. Cancer Biol. 1995; 6: 203-209Crossref PubMed Scopus (32) Google Scholar, 2Wera S. Hemmings B.A. Biochem. J. 1995; 311: 17-29Crossref PubMed Scopus (597) Google Scholar, 3Schönthal A.H. Semin. Cancer Biol. 1995; 6: 239-248Crossref PubMed Scopus (35) Google Scholar, 4Mumby M.C. Walter PubMed Scopus Google Scholar, S. Semin. Cancer Biol. 1995; 6: PubMed Scopus Google One of the studied of this is protein phosphatase type 2A (PP2A), protein phosphatase type protein phosphatase type an and in its S. PubMed Scopus Google role in cell growth regulation has been by in PP2A has been to a of a that is for cell (1Lee T.H. Semin. Cancer Biol. 1995; 6: 203-209Crossref PubMed Scopus (32) Google the and of the and PP2A M.C. 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