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The Role of P300-Dependent MYC Acetylation in MYC Functions

  • Author(s): Vorontchikhina, Marina
  • Advisor(s): Martinez, Ernest
  • et al.
Abstract

ABSTRACT OF THE DISSERTATION

The Role of P300-Dependent MYC Acetylation in MYC Functions

by

Marina Vorontchikhina

Doctor of Philosophy, Graduate Program in Cell, Molecular and Developmental Biology

University of California, Riverside, December 2011

Dr. Ernest Martinez, Chairperson

The MYC oncoprotein regulates transcription of a multitude of downstream target genes triggering various biological outcomes, such as the induction of cellular proliferation, apoptosis, and oncogenic transformation. While MYC protein levels and activity are tightly controlled in normal cells, MYC is deregulated in most human malignancies. Since cancer is one of the leading causes of death worldwide, it is vital to elucidate the molecular and biochemical mechanisms underlying the modification and regulation of the MYC protein, whose overexpression contributes to the development of most malignant tumors. Posttranslational modifications are implicated in the regulation of MYC stability and function. For instance, several co-activators/histone acetyltransferases (HATs) have been shown to bind and acetylate the MYC protein affecting its turnover by the proteasome. Co-activator/HAT p300 interacts with MYC increasing its stability and transactivation functions. However, once p300 acetylates the oncoprotein at seven lysine residues, MYC becomes more unstable due to induced degradation via the proteasome pathway. While MYC acetylation has been established, the role of acetylation in MYC biological functions has not been determined. Here, I report that by using site-directed mutagenesis I have identified lysine 158 in MYC as the major residue acetylated by the p300. I also demonstrate that acetylation of K158 reduces MYC-activated apoptosis which could be related to MYC-dependent regulation of certain pro-apoptotic genes associated with mitochondrial function, as it was shown by Real-time quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) analysis. Furthermore, I demonstrate that MYC transcriptionally activates p300 in mammalian cells and, by using Luciferase reporter assays, I further show that MYC and co-activator p300 synergistically activate the promoter of the Cyclin D2 (CCND2), a well-known cell cycle regulatory gene. Moreover, by utilizing immunoprecipitation methods, I establish a link between MYC acetylation by p300 and its interaction with the co-activator/HAT, TIP60. Other cell and molecular biology procedures, such as immunofluorescence and RNA interference, were used in this study as well. These findings begin to uncover a role of co-activator/HAT p300 in MYC biological functions and are important because they suggest potential new targets for the treatment of MYC-dependent cancers.

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