OCT 23, 2013 12:00 PM PDT

Cellular regulation of the molecular chaperone HSP90 by posttranslational modifications - impact on function and drug sensitivity

Speakers
  • Senior Investigator, National Cancer Institute, Center for Cancer Research
    Biography
      Dr. Neckers received his Ph.D. from the University of Connecticut, completed postdoctoral training at the NIH, and joined the NCI in 1981. He became Chief of the Tumor Cell Biology Section, Medicine Branch, in 1988. An early proponent of translational research, Dr. Neckers pioneered development of oligonucleotide-based therapeutic strategies. Recently, Dr. Neckers has been investigating the role of chaperone proteins in signal transduction. His identification of benzoquinone ansamycins as specific antagonists of the chaperone HSP90 uncovered the importance of this protein for the growth and survival of cancer cells and led directly to the first phase I clinical trial of an HSP90 antagonist as an anticancer agent. Dr. Neckers continues to examine the pivotal role of Hsp90 in cancer cell survival, and participates in the ongoing translational development of Hsp90 inhibitors as novel anti-cancer agents. Dr. Neckers holds several patents and has been the recipient of several NIH Merit and NIH Inventor's Awards.

    Abstract:

    Molecular chaperones help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of aggregation in the protein-rich intracellular environment. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that participates in stabilizing and activating more than 200 proteins - referred to as Hsp90 ‘clients' - many of which are essential for constitutive cell signalling and adaptive responses to stress. To accomplish this task, Hsp90 and additional proteins termed co-chaperones form a dynamic protein complex known as the Hsp90 chaperone machine. The complex nature of Hsp90 regulation and the many ways in which it participates in cell physiology have been clarified in recent years, in part with the help of small molecule Hsp90 inhibitors. Considerable progress has been made in understanding the dynamic conformational flexibility of Hsp90 and in recognizing the importance of post-translational modifications in regulating Hsp90 function. Hsp90 function has been co-opted by cancer cells to preserve their survival in the face of numerous environmental insults, and growing clinical evidence suggests a benefit for targeting Hsp90, alone or in combination with other agents, in cancer.


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