The Laboratory of Cell Biology (LCB) studies the processing, transport, and metabolism of proteins and small molecules related to malignant transformation, metastasis, and multidrug resistance in cancer. The principal investigators of the laboratory, who are experts in molecular biology, genetics, biochemistry, structural biology, cellular regulation of cell growth and metabolism, resistance to anticancer drugs, and the physics of cell-matrix interactions, work on research projects related to those topics. The Multidrug Resistance Section studies the molecular basis of anticancer drug resistance, while the Transport Biochemistry Section investigates the biochemistry of energy-dependent transporters. Post-translational regulation of the tumor suppressor p53 and the roles of Wip1 in promoting cellular proliferation are the focus of the Chemical Immunology Section, while the DNA and Nucleoproteins Section is involved in computational and experimental studies of nucleic acid-protein interactions. The Biochemistry of Proteins Section studies the role of ATP-dependent proteolysis in multiple cellular processes. The Biophysics Section develops novel EM-based approaches to determine single molecule and multisubunit structures. The Tissue Morphodynamics Unit studies how normal and cancer cells modify their environments to promote normal differentiation and cancer cell metastasis. Finally, the Crystallography Section works on X-ray crystallography of membrane proteins and protein complexes.
LCB also includes three Cores, one involved in 3D electron microscopy, one in molecular modeling, and one in characterization of post-transcriptional protein processing. Joint journal clubs and data presentations among some sections, and laboratory-wide research seminars facilitate the sharing of expertise and help to foster collaborations among members. LCB investigators have contributed to characterizing important cellular processes involved in the development, prevention and/or treatment of cancer. For example, the multidrug transporter, an energy-dependent efflux pump (ABC transporter) for many different cytotoxic chemotherapeutic drugs that contributes to drug resistance of approximately half of all human cancers, was cloned and characterized in the laboratory and new ABC transporters and other mechanisms involved in drug resistance have been characterized. Two bacterial ATP-dependent proteases, LON and CLP, which have mammalian mitochondrial homologs, have been characterized and shown to share structural and catalytic features with mammalian proteosomes that are responsible for energy-dependent regulation of proteolysis in mammalian cells. The alternate metabolic pathways involved in melanin biosynthesis, a natural pigment that protects against UV-related DNA damage, have been defined. The structural requirements for binding of peptides to class I and class II major histocompatibility complex (MHC) molecules have been determined, and this information is being applied to the production of anticancer vaccines. The observation that Wip1 is overexpressed in several human cancers motivates the development of specific inhibitors that selectively target its activity. Structural analysis of membrane proteins and protein complexes involved in energy generation, cancer, and HIV has been advanced using computational, X-ray and high-resolution EM approaches.
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Symposium held in September:
Celebrating 30 Years of Research on Multidrug Resistance and ABC Transporters
September 22-23, 2016, NIH Campus, Building 35, Room 620-630
The discovery and characterization of P-glycoprotein as a mechanism of multidrug resistance is widely accepted as a seminal contribution to the ongoing effort to end death and alleviate suffering caused by cancer. In honor of the 30th anniversary of the cloning of the human MDR1 (ABCB1) gene, we held a day-and-a-half scientific symposium on the NIH campus in Bethesda, Maryland, on September 22 and 23, 2016. This event included current and former members of the MDR group in the Laboratory of Cell Biology, as well as collaborators and colleagues in the field. The first day of scientific talks and discussions was followed by a dinner in celebration of this anniversary.