The Mechanism of Myc Function in Cell Proliferation and Cancer
Lead Research Organisation:
University of Dundee
Department Name: College of Life Sciences
Abstract
One in three people will have cancer during their lifetime. I investigate how cancer arises, because to treat it effectively, it is critical to know how we get the disease. A protein called Myc plays a prominent role in many human cancers. My research asks, How does Myc increase our risk of cancer?
Over 20 years ago Myc was found to be a transcription factor, which means that it transcribes the DNA that codes for particular genes into messages. Those messages code for the synthesis of proteins that make up the cell. We want to know which genes Myc transcribes to drive cancer. Myc is actually a rather weak transcription factor, and I therefore started to search for other functions that Myc might have. This led me to discover that Myc regulates genes twice - not only does it increase the amount of message produced, it also increases the amount of protein produced from each message.
This finding means that we have missed many of the significant genes that Myc activates. I want to find the novel Myc-activated genes and discover what they do in cancer cells. These genes will be new targets for cancer therapies.
Over 20 years ago Myc was found to be a transcription factor, which means that it transcribes the DNA that codes for particular genes into messages. Those messages code for the synthesis of proteins that make up the cell. We want to know which genes Myc transcribes to drive cancer. Myc is actually a rather weak transcription factor, and I therefore started to search for other functions that Myc might have. This led me to discover that Myc regulates genes twice - not only does it increase the amount of message produced, it also increases the amount of protein produced from each message.
This finding means that we have missed many of the significant genes that Myc activates. I want to find the novel Myc-activated genes and discover what they do in cancer cells. These genes will be new targets for cancer therapies.
Technical Summary
The Mechanism of Myc Function in Cell Proliferation and Cancer
c-Myc expression is elevated in a significant proportion of cancers, and experimental Myc overexpression promotes tumour formation. Myc is also essential for cell proliferation. Despite the fact that Myc has a critical role in cell proliferation and transformation, we know little about the function of Myc during these processes. Myc is a transcription factor and it is via transactivation of target genes that Myc is presumed to function. Recently, I have found a novel biochemical function of Myc which is to promote mRNA cap methylation, a modification necessary for mRNA translation. To my knowledge, this is the first observation that a transcription factor can upregulate gene expression by increasing mRNA cap methylation. My research focus will be to biochemically characterise this novel Myc function and to investigate its role in Myc-induced cell proliferation and transformation. I will address:
1. What is the mechanism by which Myc promotes mRNA cap methylation?
2. What is the physiological significance of Myc-induced mRNA cap methylation?
3. Are Myc mutants found in cancers hyperactive for mRNA cap methylation?
Mechanistic characterisation of this pathway will be carried out using co-immunoprecipitations, chromatin immunoprecipitations and by manipulating expression of pathway components using siRNA. Global identification of Myc-induced cap methylated mRNA will be carried out by purification of these mRNAs by immunoprecipitation and affinity chromatography followed by microarray analysis. This will reveal the extent of cap methylation in response to Myc and identify which mRNAs are methylated in response to Myc. My preliminary studies have demonstrated that Myc can upregulate two genes by simultaneous upregulation of transcription and mRNA cap methylation. The proposed microarray studies will reveal whether the majority of Myc transcriptional target genes are also subject to Myc-induced cap methylation.
I will investigate the significance of Myc-induced cap methylation in Myc-induced cell proliferation and transformation. Following identification of Myc-induced cap methylated mRNAs, I will investigate whether particular cellular pathways relevant to cell proliferation and transformation are targetted by this mechanism. I will select candidate mRNAs and determine whether they are required for Myc-induced cell proliferation and transformation in cell-based assays. I will also investigate whether Myc-induced cap methylation is hyperactivated by Myc mutants found in cancer.
The objective of this study is to better define the role of Myc in cancer with the long term goal of targetting Myc function in cancer therapies.
c-Myc expression is elevated in a significant proportion of cancers, and experimental Myc overexpression promotes tumour formation. Myc is also essential for cell proliferation. Despite the fact that Myc has a critical role in cell proliferation and transformation, we know little about the function of Myc during these processes. Myc is a transcription factor and it is via transactivation of target genes that Myc is presumed to function. Recently, I have found a novel biochemical function of Myc which is to promote mRNA cap methylation, a modification necessary for mRNA translation. To my knowledge, this is the first observation that a transcription factor can upregulate gene expression by increasing mRNA cap methylation. My research focus will be to biochemically characterise this novel Myc function and to investigate its role in Myc-induced cell proliferation and transformation. I will address:
1. What is the mechanism by which Myc promotes mRNA cap methylation?
2. What is the physiological significance of Myc-induced mRNA cap methylation?
3. Are Myc mutants found in cancers hyperactive for mRNA cap methylation?
Mechanistic characterisation of this pathway will be carried out using co-immunoprecipitations, chromatin immunoprecipitations and by manipulating expression of pathway components using siRNA. Global identification of Myc-induced cap methylated mRNA will be carried out by purification of these mRNAs by immunoprecipitation and affinity chromatography followed by microarray analysis. This will reveal the extent of cap methylation in response to Myc and identify which mRNAs are methylated in response to Myc. My preliminary studies have demonstrated that Myc can upregulate two genes by simultaneous upregulation of transcription and mRNA cap methylation. The proposed microarray studies will reveal whether the majority of Myc transcriptional target genes are also subject to Myc-induced cap methylation.
I will investigate the significance of Myc-induced cap methylation in Myc-induced cell proliferation and transformation. Following identification of Myc-induced cap methylated mRNAs, I will investigate whether particular cellular pathways relevant to cell proliferation and transformation are targetted by this mechanism. I will select candidate mRNAs and determine whether they are required for Myc-induced cell proliferation and transformation in cell-based assays. I will also investigate whether Myc-induced cap methylation is hyperactivated by Myc mutants found in cancer.
The objective of this study is to better define the role of Myc in cancer with the long term goal of targetting Myc function in cancer therapies.