Research at LICR Oxford
- Prof. Xin Lu
- Prof. Colin Goding
- Prof. Peter Ratcliffe
- Dr Gareth Bond
- Dr John Christianson
- Dr Sarah De Val
- Dr Skirmantas Kriaucionis
- Dr Panagis Filippakopoulos
The role of the ASPP proteins in neuronal stem cells and the development of disease with neuronal origin
Signalling pathways that regulate autophagy via the ASPP proteins
Crosstalk between the Wnt and p53 signalling pathways and their effects on tumour metastasis
The role of the ASPP proteins in regulating cell polarity, cancer initiating cells (cancer stem cells) and tumourigenesis
Crosstalk between the ASPP proteins and Notch signalling in cell fate determination
Identification of therapeutic targets in the ASPP pathway
The main goal of our research is to identify molecular mechanisms that suppress tumour growth and metastasis.
Over the past few years we have continued to investigate how p53 is regulated. By generating and characterising a Ser312Ala knock-in transgenic in vivo model, we have demonstrated for the first time that phosphorylation of p53 at Ser312 contributes to its tumour suppressive ability in vivo. We have also demonstrated that ASPPs are molecular switches of cell fate (i.e. cell polarisation, proliferation/migration and differentiation). This is supported by the findings that: 1) by binding to p53 and altering its promoter selectivity, the ASPP proteins selectively stimulate (ASPP1, ASPP2) or inhibit (iASPP) p53-induced apoptosis in cancer cells; 2) in a transgenic in vivo model system, ASPP2 is a haploinsufficient tumour suppressor; and 3) in development, ASPP2 binds Par3 to control cell polarity and promotes epithelial differentiation.
Most recently, we have observed that the ASPPs are regulated by differentiation signals both in vitro and in vivo, and function at different cellular sites. Mechanistically, ASPP2’s N-terminus can bind Par3 and Ras at the cell surface, whereas its C-terminus binds nuclear p53. The dynamic nature of ASPP localisations, together with their unique structural motifs, make them ideal molecular switches to survey and integrate signals between the cell surface and nucleus, to control transcription and determine cell fate. Our current work is, therefore, focussed on using recently generated conditional ASPP2 and iASPP transgenic in vivo models to 1) elucidate the biological importance and molecular mechanisms of cell polarity in tumour suppression and metastasis; and 2) identify molecular switches that survey and integrate signals from the cell surface to transcription and cell fate determination.
Slee EA, Benassi B, Goldin R, Zhong S, Blandino G and Lu X. (2010) Phosphorylation of Ser312 contributes to tumour suppression by p53 in vivo. Proc. Natl. Acad. Sci. USA 107:19479-84.
Sottocornola R, Royer C, Vives V, Tordella L, Zhong S, Wang Y, Ratnayaka I, Shipman M, Cheung A, Ferretti P, Molnár Z, and Lu X. (2010) ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development. Dev. Cell 19: 126-37.
Wang XD, Lapi E, Sullivan A, Ratnayaka I, Goldin R, Hay R and Lu X. (2010) SUMO-modified nuclear cycin D1 bypasses Ras-induced senescence. Cell Death Differ. [In press].
Bergamaschi D, Samuels Y, Sullivan A, Zvelebil M, Breyssens H, Bisso A, Del Sal G, Syed N, Smith P, Gasco M, Crook T and Lu X. (2006) iASPP preferentially binds the p53 proline-rich region and modulates apoptotic function of p53 polymorphic at codon 72. Nat Genet 38:1133-1141.
Vives V, Su J, Zhong S, Ratnayaka I, Slee E, Goldin R, Lu X. (2006) ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth. Genes Dev 20:1262-1267.
Trigiante G, Lu X. (2006) ASPPs and cancer. Nat Rev Cancer 6:217-226.
Bergamaschi D, Samuels-Lev Y, O'Neil N, Crook T, Trigiante G, Hsieh JK, O’Connor DJ, Zhong S, Campargue I, Thompson M, Kuwabara P and Lu X. (2003) iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genet Vol.33: 162-167.
Vousden KH, Lu X. (2002) Live or let die: the cell's response to p53. Nat Rev Cancer 2:594-604.
Samuels-Lev Y, O'Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S, Campargue I, Naumovski L, Crook T, Lu X. (2001) ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell 8:781-794.