OCT 11, 2018 9:00 AM PDT

Destabilization and Degradation of MYC: More Ways Than One

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Post-Doctoral Fellow, Princess Margaret Cancer Research, University Health Network
    Biography
      Dr. Jason De Melo is a post-doctoral fellow in the laboratory of Dr. Linda Penn at the Princess Margaret Cancer Centre in Toronto, Canada where his work focuses on elucidating a new degradation pathway for the MYC oncoprotein. Prior to his current position, Jason graduated from the University of Waterloo with a B.Sc in Biochemistry with a specialization in Biotechnology. His studies included work placements at Environment Canada, the Public Health Agency of Canada and Lorus Therapeutics. Jason then moved to McMaster University where he studied under the supervision of Dr. Damu Tang, graduating with a Ph.D. in Medical Sciences. Jason's work examined the role of SHARPIN in the regulation of the tumoursuppressor PTEN in Breast Cancer. In addition to his research work, Jason now teaches a course on Genome Editing at the Michener Institute for Education at UHN.

    Abstract

    The oncogenic transcription factor c-MYC (MYC) is deregulated, and often overexpressed, in more than 50% of cancers. MYC deregulation is associated with poor prognosis and aggressive disease, suggesting that the development of therapeutic inhibitors targeting MYC would dramatically impact patient care and outcome. MYC is a highly regulated transcription factor, with a protein and mRNA half-life of approximately 30 min. The most extensively studied pathway regulating MYC protein stability involves ubiquitylation and proteasomal degradation mediated by the E3-ligase, SCFFbxw7. We provide evidence for a SCFFBXW7-independent regulatory mechanism centered on Lysine 52 (K52) within MYC Box I (MBI) of the MYC protein. This residue has been shown to be post-translationally modified by both ubiquitylation and SUMOylation, hinting at the interplay of post-translational modifications at this site, and the importance of this residue. We demonstrate that mutation of K52 to arginine (R) renders the MYC protein more labile. Mechanistically, we show that the degradation pathway regulated by K52 is independent of the Cullin-Ring-Ligase (CRL) family of E3-ligases, which includes not only the canonical SCFFBXW7, but also a number of other known MYC-targeting E3-ligases, such as SCFSKP2, SCFβTCRP, SCFFBXO28 and DCXTRUSS. To characterize this degradation pathway further we will utilize unbiased and targeted experiments to elucidate the proteins involved. Taken together, our data identifies a novel regulatory pathway centred on K52 that may be exploited for the development of anti-MYC therapeutics. 

    Learning Objectives: 

    1. Learn about the critical role of MYC in tumorigenesis
    2. Understand the relationship between the amount of MYC protein in the cell and its tumorigenicity
    3. Understand how the stability of the MYC protein is regulated in the cell


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