Professor Anna Philpott
Proneural transcription factors
Hutchison/MRC Research Centre, Cambridge Biomedical Campus
We aim to characterise mechanisms that co-ordinate cell cycling with stem cell maintenance and differentiation during development, homeostasis and disease. In particular, we have uncovered a conserved regulatory mechanism where cdk-dependent phosphorylation of multiple proneural proteins promotes maintenance of progenitor/stem status, while dephosphorylation drives differentiation.
Our future aims are three-fold: we will further characterise the molecular mechanisms that link cell cycling and differentiation: We will use this understanding to develop methods potentiating the directed differentiation of proneural protein-regulated tissues, including neurons and pancreatic islets: We will also investigate perturbation of the balance between stem-ness/progenitor maintenance and differentiation that is a frequent hallmark of multiple cancers, focussing on molecular regulation of proliferation and differentiation in neuroblastoma, glioblastoma and insulinoma, with the aim of developing new therapeutic strategies.
|Aoibheann McNally||Roberta Azzarelli|
|Magdalena Sznurkowska||John Davies|
|Fahad Ali||Laura Hardwick|
|Sebastien Gillotin||Goran Tomic|
|Daniel Marcos Corchado|
Controlling the balance between division of cells and the process of differentiation, whereby cells stop dividing and adopt their specialised function, is critical both in development and in adult tissues that must maintain and repair themselves. Moreover, in many cancers and in particular cancers of children, this balance is disrupted. We are investigating the role of a class of proteins, the proneural factors, in controlling cell division and differentiation, and how their activity is controlled by chemical modification in response to their cellular environment. We are: - Studying how chemical modification of proneural proteins controls cell division versus differentiation in the nervous system, pancreas and gut. - Investigating how proneural proteins work to turn on different genes to either promote cell division or arrest it, depending on the environment the cells are in. - Developing treatments for the childhood cancer neuroblastoma by changing the chemical modification of proneural proteins using new drugs. In the longer term, our understanding of the control of this crucial class of proteins, the proneurals, will help us to turn stem cells into useful tissues such as nerve and pancreas, as well as aid us in rational development of new therapies for cancers where proneural protein activity has been disrupted.
- Wylie LA, Hardwick LJ, Papkovskaia TD, Thiele CJ, Philpott A. (2015) Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma. Dis Model Mech. 8, 429-41. PMCID:PMC4415893
- Ali FR, Cheng K, Kirwan P, Metcalfe S, Livesey FJ, Barker RA, Philpott A (2014) The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro. Development. 141, 2216-24. PMID:24821983
- Hindley C, Ali F, McDowell G, Cheng K, Jones A, Guillemotand F, Philpott A (2012) Post-translational modification of Ngn2 differentially affects transcription of distinct targets to regulate the balance between progenitor maintenance and differentiation Development, 139, 1718-23. PMCID:PMC3328174
- Ali F, Hindley C, McDowell G, Deibler GR, Jones A, Kirschner M, Guillemot F, Philpott A (2011) Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis. (2011). Development 138, 4267-77. PMCID:PMC3171226
- Vosper JM, McDowell GS, Hindley CJ, Fiore-Heriche CS, Kucerova R, Horan I, Philpott A (2009) Ubiquitination on canonical and non-canonical sites targets the transcription factor neurogenin for ubiquitin-mediated proteolysis. Journal of Biological Chemistry, 284, 15458-68. PMCID:PMC2708843