c-myc is a protooncogene deregulated in a wide range of human cancers. Aberrant Myc expression due to amplifications or translocations is often associated with tumour aggressiveness and poor prognosis.
Importantly, even transient inactivation of Myc is suff icient to inhibit growth of certain tumours making Myc a particularly interesting protein for therapeutic targeting. Involvement of the ubiquitin pathway in regulating Myc function provides a valuable opportunity to modulate activity of this protein.
We propose to identify novel regulators of Myc stability through genome-wide siRNA library screens using fluorescence-based sorting. Based on previous studies, identified molecules will include enzymes that modify Myc directly, such as kinases or acetylases, and may include components of the degradation pathways, such as deubiquitinating enzymes (DUBs).
Many of these enzymes are either known to be suited for pharmacological inhibition (e.g. kinases) or are expected to be so (DUBs are isopeptidases and such enzyme s can be inhibited with small molecules). We expect that this project will define a feasible strategy to target deregulated Myc function in human cancers.
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