The function of c-myc and RNA cap methylation

Research

The function of c-myc

Victoria Cowling’s group investigates how c-Myc oncogene functions biochemically and the signalling pathways it regulates to drive cell proliferation and tumour formation. Currently the group is investigating the mechanism and biological significance of c-Myc induced mRNA cap methylation, an essential step in mRNA translation.

c-Myc is essential for almost all mammalian cells to grow and proliferate. It is upregulated by growth factors and probably drives cell proliferation by co-ordinately regulating the expression of a number of genes and signalling pathways. Myc can also function as an oncogene; when Myc expression is deregulated it promotes unrestrained cell growth and proliferation. In addition, elevated Myc expression promotes apoptosis and growth arrest, both of which have the potential to restrict Myc oncogenic function. Our research focus is to investigate how Myc drives these diverse biological responses. We study both how Myc functions biochemically, and the signalling pathways it activates.

Myc proteins function biochemically as a weak but pleiotropic transcription factors. We recently found that Myc also regulates gene expression by a novel mechanism, that is by promoting methylation of the 5’mRNA cap, an essential step for mRNA translation. This revealled that although Myc is a weak transcription factor it is rather efficient at upregulating expression of specific proteins via the combined the effects of increased transcription and increased mRNA cap methylation and translation. We are currently investigating which proteins are best upregulated by this dual mechanism and the role of these proteins in mediating the biological effects of Myc. We also made the unexpected finding that, for a subset of genes, Myc can upregulate mRNA cap methylation and protein expression independently of transcription. We are investigating the identity and function of this novel set of Myc targets. In addition, we are studying the mechanism of Myc-induced mRNA cap methylation and how other signalling pathways and transcription factors influence this essential step in gene regulation.

Publications

Gonatopoulos-Pournatzis T, Bounds R, and Cowling VH (2011) RAM/Fam103a1 is required for mRNA cap methylation  Molecular Cell (in press)  

Cowling VH (2009) Enhanced mRNA cap methylation increases Cyclin D1 expression and promotes cell transformation Oncogene 2009, Nov16 epub PMID: 19915615

Cowling VH (2009) Regulation of mRNA cap methylation Biochemical Journal 2009, Dec 18th epub

Fernandez-Sanchez ME, Gonatopoulos-Pournatzis T, Preston G, Lawlor MA, and Cowling VH (2009) S-Adenosyl Homocysteine Hydrolase (SAHH) is required for Myc-induced mRNA cap methylation, protein synthesis and cell proliferation Mol Cell Biol 2009, Dec;29(23):6182-91. Epub 2009 Oct 5.

Cole MD and Cowling VH (2009) Specific regulation of mRNA cap methylation by the c-Myc and E2F1 transcription factors Oncogene 2009 Mar 5;28(9):1169-75. Epub 2009 Jan 12.

Cole MD and Cowling VH (2008) Transcription-independent functions of MYC: regulation of translation and DNA replication Nature Reviews Mol Cel Biol 2008 Oct; 9 (10):810-5. Epub 2008 Aug 13.