Selectively killing cancer cells is a major challenge in cancer therapy. Our group’s focus is understanding how to selectively activate the tumour suppressor p53 to kill cancer cells. This has led to our identification of the evolutionarily conserved ASPP family of proteins. The three ASPP members (ASPP1, ASPP2 and iASPP) act as molecular switches of cell fate by regulating the target selectivity of p53 and its siblings (p63 and p73). By controlling transcriptional target selectivity and cell polarity, the ASPPs determine whether a cell undergoes cell differentiation, proliferation, autophagy or apoptosis. Thus the ASPP family of proteins are emerging as new biomarkers and excellent targets for the development of novel anti-cancer therapies.
Recently, we observed that the ASPPs play fundamental roles in regulating cell polarity and epithelial stratification. Our finding that the tumour suppressor ASPP2 is a novel regulator of cell polarity has established a new link between cell polarity and tumour suppression. We have also recently observed that ASPP2 is a novel regulator of autophagy, which dictates the cell’s response to the activity of the Ras oncogene.
Most recently, we have observed that the ASPPs are highly expressed in epithelial cells, and are regulated by cell proliferation and 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 membrane, whereas its C-terminus binds nuclear p53. Similarly, phosphorylation of iASPP by cyclin B/cdk1 at its N-terminus promotes its entry into the nucleus and enhances p53’s ability to bind to its C-terminus. The dynamic nature of the localizations of the ASPPs within the cell, together with their unique structural motifs, makes them ideally placed to survey and integrate signals between the cell membrane and nucleus, i.e., controlling transcription and determining cell fate.
A key question in cancer research is why more than 80% of human tumours are epithelial in origin. As p53 is inactivated in most human epithelial tumours, the identification of the ASPP family of proteins as key regulators of cell polarity and adhesion at the cell membrane, and transcriptional co-factors of p53 in the nucleus, provides us with a unique opportunity to investigate whether cell polarity is a checkpoint of tumour suppressions. We are studying how cell polarity integrates p53, WNT and Notch signalling pathways to regulate epithelial plasticity and cell fate determination.
Tordella L, Koch S, Salter V, Pagotto A, Doondeea JB, Feller SM, Ratnayaka I, Zhong S, Goldin RD, Lozano G, McKeon FD, Tavassoli M, Fritzsche F, Huber GF, Rössle M, Moch H, Lu X. ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63 Proc Natl Acad Sci U S A. 2013 Oct.
Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, Ratnayaka I, Sullivan A, Brown NR, Endicott J, Knapp S, Kessler BM, Middleton MR, Siebold C, Jones EY, Sviderskaya EV, Cebon J, John T, Caballero OL, Goding CR, Lu X. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell. 2013 May 13;23(5):618-33.
Wang Y, Wang XD, Lapi E, Sullivan A, Jia W, He YW, Ratnayaka I, Zhong S, Goldin RD, Goemans CG, Tolkovsky AM, Lu X. Autophagic activity dictates the cellular response to oncogenic RAS. Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13325-30.
Notari M, Hu Y, Koch S, Lu M, Ratnayaka I, Zhong S, Baer C, Pagotto A, Salter V, Candi E, Melino G and Lu X (2011). iASPP prevents premature cellular senescence and is required for normal epithelial stratification. Proc Natl Acad Sci USA. Oct 4;108(40):16645-50.
Sottocornola R, Royer C, Vives V, Tordella L, Zhong S, Wang Y, Ratnayaka I, Shipman M, Cheung A, Gaston-Massuet C, Ferretti P, Molnár Z, Lu X. ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development. Dev Cell. 2010 Jul 20;19(1):126-37.
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.