Mutant p53 regulates invasion via integrins and EGFR
Patricia Muller1, Patrick Caswell1, Brendan Doyle1, Saadia Karim1, Owen Sansom1, Natalia Lukashchuk1, David Gillespie1, Pauline Gisselin2, Anne Cromer2, Marcin Iwanicki2, Joan Brugge2, Jim Norman1, Karen Vousden1
1The Beatson institute for Cancer Research, Glasgow, UK, 2Harvard Medical School, Boston, Massachusetts, USA
Background
Point
mutations in the tumor suppressor protein p53 are frequently observed in about
half of all tumors. The majority of these mutations are localized in the DNA
binding domain of p53 and have been shown to dominant negatively suppress WT
p53 functions. Recent studies furthermore revealed that mutations in p53 result
in a protein that has acquired a novel function in promoting metastasis. In the
present work we therefore aimed to elucidate the mechanisms that underlie this
enhanced metastatic potential of mutant p53
Methods
Using
H1299 cells that lack WT p53 expression, we studied the effects of frequently
occurring mutations in p53 (175H and 273H) on invasion.
Results
We
observed that mutations in p53 promote the invasion of cells into matrigel
independently of the presence of WT p53. Additionally, mutant p53 cells moved
randomly into a wounded area as opposed to persistent movement of control
cells. Enhanced invasion and random movement have been associated with
increased signalling via integrins and epidermal growth factor receptor (EGFR)
and an increased recycling of both the integrin receptor and the EGFR was
observed in our mutant p53 cells. This recycling was dependent on the
expression of RAB coupling protein (RCP) and resulted in a constitutive
phosphorylation of EGFR at residue 845 and a concomitant downstream signalling
to AKT.
A knockdown of the p53 related proteins p63, but not p73, in WT p53 null cells enhanced the invasion of cells in matrigel and caused random movement of cells in wound healing assays. Conversely, overexpression of p63 in mutant p53 cells inhibited invasion.
Conclusions
Our
findings suggest a novel role for mutant p53 in driving invasion via inhibition
of the normal suppressive functions of p63 in invasion and open the possibility
that blocking integrin and/pr EGFR might have therapeutic benefit in mutant
p53 expressing cancers.
