Michael M. Gottesman Lab

Michael M. Gottesman, M.D., Chief, Laboratory of Cell Biology, Chief, Molecular Cell Genetics Section
Laboratory of Cell Biology
Building 37 Room 1B22
National Cancer Institute
Bethesda, Maryland 20892
Phone: (301) 496-1530
Fax: (301) 402-0450
Email: GOTTESMM@DC37A.NCI.NIH.GOV

Brief Biography

Dr. Gottesman obtained his M.D. from Harvard Medical School, completed his internship and residency in medicine at the Peter Bent Brigham Hospital in Boston, and received his postdoctoral research training in molecular genetics with Martin Gellert at the NIH. After a year as an Assistant Professor in the Department of Anatomy at Harvard Medical School he moved to the NIH in 1976. He currently serves as the NIH Deputy Director for Intramural Research as well as Chief of the Laboratory of Cell Biology.

Research interests

Project Title: Analysis of Multidrug Resistance in Cancer

Success in treatment of some disseminated cancers with chemotherapy has led to intensified efforts to understand why many other cancers are intrinsically resistant to anti-cancer drugs or become resistant to chemotherapy after many rounds of treatment. Work in the Molecular Cell Genetics Section of the Laboratory of Cell Biology has revealed that a major mechanism of resistance of cancer cells to natural product anti-cancer drugs such as Adriamycin, etoposide, vinblastine, actinomycin D and taxol is expression of an energy-dependent drug efflux pump, termed P-glycoprotein (P-gp) or the multidrug transporter. This pump system contributes to drug resistance in about 50% of human cancers by preventing accumulation of powerful anti-cancer drugs in cancer cells. The sequence of the multidrug resistance (MDR1) cDNA determined in our laboratory has led to a model of the transporter as a pump with 12 transmembrane domains and 2 ATP sites; determination of the domains of P-gp responsible for substrate binding and coupling of ATPase activity to substrate transport are major goals of our work.
Recent studies using affinity analogs of substrates of P-gp have identified regions around the 5th and 6th and 11th and 12th transmembrane domains as major drug interaction sites. Site-specific mutagenesis of these sites has confirmed that many different mutations within these regions alter substrate specificity of the transporter. Current studies are directed towards defining in more molecular detail how the various substrate interaction sites cooperate with each other, and how they stimulate the drug-dependent ATPase activity of P-gp. Models systems used for this analysis include expression in the yeast Saccharomyces cerevisiae, MDR1 baculovirus expression vectors, retroviral expression systems, and vaccinia vectors. We have also explored the role of phosphorylation of P-gp by eliminating all known phosphorylation sites in the molecule; these mutations have little or no effect on the ability of the P-gp to confer multidrug resistance.
While the studies on substrate and inhibitor specificity of P-gp will aid in the development of new chemotherapeutic regimens and the development of agents which reverse drug resistance, an alternative way to exploit information about the multidrug transporter is to use it to confer resistance on drug-sensitive tissues such as bone marrow in patients undergoing intensive chemotherapy. This approach has been modeled in transgenic mice in which expression of the MDR1 cDNA in bone marrow makes this bone marrow resistant to toxicity of natural product anti-cancer drugs, and in animal models using retroviral vectors to confer selective advantage to transplanted, MDR1 transduced bone marrow in the presence of drugs such as taxol. Clinical trials are in progress to test this approach in patients undergoing autologous bone marrow transplantation for diseases such as breast, ovarian, and brain cancers. In collaboration with other NIH scientists, the MDR1 cDNA has also been closely linked to other therapeutic genes, such as genes need for treatment of Gaucher disease (glucocerebrosidase), Fabry disease (alpha-galactosidase), Chronic Granulomatous Disease (various subunits of the NADPH oxidase complex) and Severe Combined Immunodeficiency (adenosine deaminase and interleukin receptor gamma subunit). Bicistronic MDR1 vectors for gene therapy of AIDS are also being constructed. Tight linkage, in which selection for drug resistance invariably results in expression of the non-selected gene, can be achieved using bicistronic vectors in which the non-selected cDNA is translated from the same mRNA as the MDR1 cDNA under control of an internal ribosome entry site (IRES).
Ongoing projects in the laboratory are dedicated to elucidating other mechanisms of multidrug resistance in cancer cells. A model system for cross-resistance to cisplatin, methotrexate, and nucleotide analogs such as 5-FU has been developed in which accumulation of drugs in resistant cells is much reduced; identification of the mechanism of this phenotype is in progress. Cisplatin-resistant mutants of Saccharomyces cerevisiae have also been isolated and cDNAs responsible for this resistance have been cloned and are being characterized.

Recent Publications

  1. Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA, Pastan I.: Genetic analysis of the multidrug transporter. Annu Rev Genet 1995;29:607-649.

  2. Licht T, Aksentijevich I, Gottesman MM, Pastan I.: Efficient expression of a functional human MDR1 gene in murine bone marrow after retroviral transduction of purified hematopoietic stem cells. Blood 1995;86:111-121.

  3. Germann UA, Chambers TC, Ambudkar SV, Licht T, Cardarelli CO, Pastan I, Gottesman MM: Phosphorylation of P-glycoprotein is not essential to confer multidrug resistance. J Biol Chem 1995;in press.

  4. Sugimoto Y, Aksentijevich I, Murray G, Brady RO, Pastan I, Gottesman MM: Retroviral coexpression of a multidrug resistance gene (MDR1) and human alpha-galactosidase A for gene therapy of Fabry disease. Hum Gene Ther 1995;6:905-915.

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Last modified on December 14, 1995.