Protein Turnover and Gene Amplification: the Work of Robert T. Schimke
Year: 2007
Type: article
Abstract: The Importance of Both Synthesis and Degradation in the Control of Arginase Levels in Rat LiverJournal of Biological ChemistryVol. 239Issue 11Preview Full-Text PDF Open AccessThe Roles of Synthesis and Degradation in the Control of Rat Liver Tryptophan PyrrolaseJournal of Biological ChemistryVol. 240Issue 1Preview Full-Text PDF Open AccessSelective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells.Journal of Biological ChemistryVol. 253Issue 5Preview Full-Text PDF Open Access The Importance of Both Synthesis and Degradation in the Control of Arginase Levels in Rat Liver (Schimke, R. T. (1964) J. Biol. Chem. 239, 3808–3817) The Roles of Synthesis and Degradation in the Control of Rat Liver Tryptophan Pyrrolase (Schimke, R. T., Sweeney, E. W., and Berlin, C. M (1965) J. Biol. Chem. 240, 322–331) Selective Multiplication of Dihydrofolate Reductase Genes in Methotrexate-resistant Variants of Cultured Murine Cells (Alt, F. W., Kellems, R. E., Bertino, J. R., and Schimke, R. T. (1978) J. Biol. Chem. 253, 1357–1370) Robert Tod Schimke was born in Spokane, Washington in 1932. He attended Stanford University and received his A.B. in 1954 and his M.D. in 1958. During his medical training, he spent a year working with Journal of Biological Chemistry (JBC) Classic author Oliver Lowry (1Lowry O.H. Rosebrough N.J. Farr A.L. Randall R.J. JBC Classics.J. Biol. Chem. 1951; 193 (http://www.jbc.org/cgi/content/full/280/28/e25): 265-275Abstract Full Text PDF PubMed Google Scholar) at Washington University in St. Louis where he was introduced to biochemical research. It was during this period that Schimke learned about biochemical regulatory processes in bacteria and decided that he would explore them in eukaryotic cells. He then interned at Massachusetts General Hospital until 1960 when he joined the Biochemical Pharmacology Laboratory of the National Institute of Arthritis and Metabolic Diseases (National Institutes of Health) under the direction of JBC Editor Herbert Tabor. At the NIH, Schimke started looking at the regulation of enzyme activity and published a series of papers exploring the adaptation of urea cycle enzymes in the rat (carbamyl-phosphate synthetase, ornithine transcarbamylase, arginosuccinate synthetase, arginosuccinase, and arginase) to changes in dietary protein. It had already been recognized that enzyme activity could be increased by the administration of hormones or substrates and that often this increase in activity was due to an increase in the rate of enzyme synthesis. However, the phenomenon of enzyme stabilization, or a decrease in the rate of enzyme degradation, was not established. The studies described in the first JBC Classic were the first to report protein degradation as a regulatory process and established a new field of biochemistry. In the second JBC Classic, Schimke and his colleagues show that the increase in tryptophan pyrrolase activity resulting from the administration of hydrocortisone or tryptophan is a product of both enzyme synthesis and enzyme stabilization. Studying the time course of changing enzyme levels as well as the enzyme's incorporation and loss of isotopic amino acids in response to the two agents, the researchers showed that hydrocortisone increased the rate of tryptophan pyrrolase synthesis whereas tryptophan decreased the rate of its degradation. This led to their conclusion that “rates of enzyme synthesis are mediated by hormonal action, whereas substrates or cofactors act by altering the rate of enzyme degradation.” In 1966 Schimke left the NIH to join the faculty at Stanford University, his alma mater. He became an Associate Professor, Professor, and Chairman of the Department of Pharmacology. Subsequently he joined Stanford's Department of Biological Sciences and became its Chairman in 1978. Schimke's early work on protein turnover paved the way for his discovery that gene amplification can result in cellular resistance to cancer chemotherapy drugs. The third JBC Classic reprinted here resulted from Schimke's studies on resistance to the cancer drug methotrexate. The drug works by inhibiting the activity of dihydrofolate reductase, an enzyme whose function is essential for cell division. In early studies, Schimke noticed that the rate of dihydrofolate reductase synthesis in the AT-3000 line of methotrexate-resistant murine cells was 200–250 times greater than that of its methotrexate-sensitive parental line (2Alt F.W. Kellems R.E. Schimke R.T. Synthesis and degradation of folate reductase in sensitive and methotrexate-resistant lines of S-180 cells.J. Biol. Chem. 1976; 251: 3063-3074Abstract Full Text PDF PubMed Google Scholar). He and his colleagues showed that this increased rate of synthesis correlated with increased cellular levels of translatable dihydrofolate reductase mRNA (3Kellems R.E. Alt F.W. Schimke R.T. Regulation of folate reductase synthesis in sensitive and methotrexate-resistant sarcoma 180 cells. In vitro translation and characterization of folate reductase mRNA.J. Biol. Chem. 1976; 251: 6987-6993Abstract Full Text PDF PubMed Google Scholar). In the third JBC Classic, Schimke and his colleagues used cDNA sequences complementary to dihydrofolate reductase mRNA to quantitate dihydrofolate reductase mRNA and gene copies in both the sensitive and resistant lines. They found that the dihydrofolate reductase gene is selectively multiplied approximately 200-fold in the resistant line. Similarly, they showed that when the AT-3000 line is grown in the absence of methotrexate, it eventually loses its resistance due to a decrease in the dihydrofolate reductase gene copy number. Thus the researchers concluded that selective multiplication of the dihydrofolate reductase gene accounted for the overproduction of dihydrofolate reductase. In the paper, Schimke suggested that the extra genetic material might have resulted from a number of processes including tandem duplications, unequal exchanges between sister chromatids, disproportionate replication of specific genes, and retention of specific chromosomal fragments. The importance of this pioneering work goes well beyond resistance to chemotherapeutic agents and establishes that genomes can be quite unstable. Schimke is currently Professor Emeritus of Biological Sciences and the American Cancer Society Research Professor Emeritus at Stanford. He was president of the American Society for Biochemistry and Molecular Biology in 1988 and was a member of the editorial board and an Associate Editor for the Journal of Biological Chemistry from 1975 to 1981 and 1983 to 2002. In recognition of his many contributions to science, he received the Boris Pregal Award from the New York Academy of Sciences (1974), the W. C. Rose Award in Biochemistry from the American Nutrition Foundation (1983), the Sloan Prize from the General Motors Cancer Research Foundation (1985), and the Lila Gruber Memorial Cancer Research Award from the American Academy of Dermatology (1988). He was elected to the National Academy of Sciences in 1976 and to the Institute of Medicine in 1983. Since his retirement, Schimke has devoted much of his time to an old love, painting. In spite of a bicycle accident in 1997 that left him a quadriplegic confined to a wheelchair and with limited use of his arms and hands, he has been prolific in his art, some of which can be seen on his website (http://www.stanford.edu/group/schimke). Some of Schimke's co-authors on the Classic papers have also become accomplished biochemists. Joseph R. Bertino is currently Professor of Medicine & Pharmacology at the University of Medicine and Dentistry of New Jersey and is also Interim Director of the Cancer Institute of New Jersey. He is internationally recognized for his role in finding curative treatments for leukemia and lymphoma. Frederick W. Alt is an Investigator for the Howard Hughes Medical Institute as well as the Charles A. Janeway Professor of Pediatrics and Genetics at Children's Hospital, Harvard Medical School, and the Scientific Director for the Center for Blood Research Institute for Biomedical Research. He is an expert in the fields of immunology and cancer biology and is renowned for his research on genetic repair systems and how breakdowns in those processes can lead to cancer. Rodney E. Kellems is Professor and Chairman of the Department of Biochemistry and Molecular Biology at the University of Texas Health Science Center at Houston. His research focuses on the regulation of gene expression during mammalian development.
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1488218884