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Anna Philpott

Professor Anna Philpott



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Graduate Students

Professor Anna Philpott is pleased to consider applications from prospective graduate students.

2018 PhD opportunities:

1.CRUK Cambridge Centre MRes/PhD programme:

2. Cambridge Stem Cell Institute:

3. MRC Doctoral training programme:


Research Interests

Cell Division versus Differentiation in Development and Disease.

Mechanisms that link the cell cycle and differentiation are poorly understood, and still less is known about how developmental cues are linked to cell cycle exit. Our laboratory is interested in understanding the coordination of cell proliferation with cell fate determination and differentiation in the early Xenopus frog embryo as well as in ES cells and mouse models. This image on the right is a blastula stage Xenopus embryo showing multiple, synchronously dividing cells.

We focus particularly on development of the embryonic nervous system, along with differentiation of endocrine lineages in the gut and pancreas, where the decision to divide or differentiate is controlled by the activity of proneural transcription factors.

Recently, we have been investigating links between the core cell cycle machinery and mechanisms of differentiation. We see that cell cycle components directly control several modes of post-translational regulation of these proneural transcription factors, which in turn, regulates the balance between precursor cell maintenance and differentiation. 

Ongoing work in the lab aims to explore cell cycle-regulated control of progenitor maintenance and differentiation in more detail using both in vitro biochemical and molecular assays and in vivo models.

Cancer cells often divide precociously and lose differentiated characteristics. Our work in normal embryonic development will help us to determine how cells stop dividing and adopt a differentiated fate, and, will allow us to understand more fully how cells lose their differentiated phenotype and re-enter the cell cycle precociously during tumourigenesis.

We are currently attempting to manipulate these processes to promote cancer cell differentiation to effect remission, particularly in neurologically-derived tumours such as neuroblastoma and glioblastoma. Moreover, we are using our findings to develop more efficient protocols to potentiate stem cell differentiation, with the aim of use for replacement therapies in diseases such as Parkinson's and diabetes.

The image on the right shows embryonal carcinoma cancer cells can be induced to differentiate into neurons in vitro by expression of a proneural transcription factor that has been mutated so it can no longer be phosphorylated by cyclin-dependent kinases. GFP marks cells expressing the proneural protein, while a marker of neuronal differentiation is detected in red.

 


Publications

Pubmed journal articles - pubmed

Key publications

Neurogenin3 phosphorylation controls pancreatic endocrine differentiation and maintenance of β-cell function. Azzarelli R, Hurley C, Sznurkowska M, Gamper I, Ali F, McCracken L, Hindley C, McDuff F, Hardwick L, Jones2 K, Kemp R, Simons B, Huch M, Evan G, Winton D, Philpott A. (2017). Developmental Cell 41: 274-286.

MyoD phosphorylation on multiple C terminal sites regulates myogenic conversion activity. Hardwick LJ, Davies JD, Philpott A. (2016).  Biochem Biophys Res Commun. 481: 97-103.

New Insights Into the Role of Ubiquitylation of Proteins.  McDowell GS, Philpott A (2016). Int Rev Cell Mol Biol.325:35-88.

Multi-site phosphorylation regulates NeuroD4 activity during primary neurogenesis: a conserved mechanism amongst proneural proteins. Hardwick LJ, Philpott A (2015), Neural Dev. 10:15.

Multi-site phospho-regulation of proneural transcription factors in development and reprogramming. Philpott A (2015).  Neurogenesis. 2: e1049733

Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma.  Wylie LA, Hardwick LJA, Papkovskaia TD, Thiele CJ and Philpott A (2015).Dis Model Mech. 8:429-41.

Emergence of neuronal diversity from patterning of telencephalic progenitors.  Azzarelli R, Hardwick LJ, Philpott A. (2015). Wiley Interdiscip Rev Dev Biol. May-Jun;4(3):197-214

Phosphorylation in intrinsically disordered regions regulates the activity of Neurogenin2. McDowell GS, Hindley CJ, Lippens G, Landrieu I and Philpott A (2014). Biomed Central Biochemistry, 6,:24

Lineage selection and plasticity in the intestinal crypt.  Philpott A and Winton DJ (2014).  Curr Opinion Cell Biol. Jul 29;31C:39-45.

Complex domain interactions regulate stability and activity of closely related proneural transcription factors.  McDowell GS, Hardwick LJ and Philpott A (2014). Biochem Biophys Res Commun. Aug 8;450(4):1283-90.

Cell cycle regulation of proliferation versus differentiation in the central nervous system. Hardwick LJ, Ali FR, Azzarelli R and Philpott A (2014).  Cell Tissue Res. (2014) Cell and Tissue Research 359, 187-200.

Nervous decision-making: to divide or differentiate. Hardwick L and Philpott A (2014). Trends Genet. 30, 254-261.

The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro.  Ali FR, Cheng K, Kirwan P, Metcalfe S, Livesey FJ, Barker RA and Philpott A (2014). Development. 141, 2216-24.

The cell cycle and pluripotency. Hindley C and Philpott A (2013). Biochemical Journal  451, 135-43.

Non-canonical ubiquitylation: mechanisms and consequences.  McDowell G and Philpott A (2013).  International Journal for Biochemistry and Cell Biology. 45. 1883-1842.

Co-ordination of cell cycle and differentiation in the developing nervous system. Hindley C and Philpott A  (2012). Biochemical Journal 444, 375-82.

Neuroblastoma progress on many fronts: the Neuroblastoma Research Symposium. Wylie L, Philpott A (2012). Pediatric Blood and Cancer. 58:649-51.

Post-translational modification of Ngn2 differentially affects transcription of distinct targets to regulate the balance between progenitor maintenance and differentiation.  Hindley C, Ali F, McDowell G, Cheng K, Jones A, GuillemotF and Philpott A (2012). Development,139, 1718-23.

Complex regulation controls Neurogenin3 proteolysis. Roark R, Itzhaki L and Philpott A  (2012).  Biology Open, 1264-72.

Regulation of cell fate determination by Skp1-Cullin1-f Box (SCF) E3 ubiquitin ligases. *Hindley CJ, McDowell GS, Wise H, Philpott A (2011). International Journal of Developmental Biology. 55:249-60.

Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis. Ali F, Hindley C, McDowell G, Deibler R, Jones A, Kirschner M, Guillemot F and Philpott A (2011). Development 138, 4267-77.

Hes6 is required for the neurogenic activity of neurogenin and NeuroD. Murai K, Philpott A and Jones PH (2011).  PLoS One. 6:e27880.

 

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