Control of cell migration: a tumour suppressor function for p53?

Abstract

Much remains to be learned about how cancer cells acquire the property of migration, a prerequisite for invasiveness and metastasis. Loss of p53 functions is assumed to be a crucial step in the development of many types of cancers, leading to dysregulation of cell cycle checkpoint controls and apoptosis. However, emerging evidence shows that the contribution of the tumour suppressor p53 to the control of tumorigenesis is not restricted to its wellknown anti-proliferative activities, but is extended to other stages of cancer development, i.e. the modulation of cell migration. This interesting alternative function has been proposed in light of the effect of p53 on specific features of migrating cells, including cell spreading, establishment of cell polarization and the production of protrusions. The effects of p53 on cell motility are largely mediated through the regulation of Rho signalling, thereby controlling actin cytoskeletal organization. These recent studies connect the regulation of proliferation to the control of cell migration and define a new concept of p53 function as a tumour suppressor gene, suggesting that p53 might be involved in tumour invasion and metastasis. This review focuses on emerging data concerning the properties of p53 that contribute to its atypical role in the regulation of cell migration.

The Role of JMY in p53 Regulation.

“…This affirms the accumulation of evidences demonstrating that p53 has a role as inhibitor of cell motility ( Figure 5) [30]. P53 has been found to be associated with tubulin, vimentin, F-actin and tubulin indicating a possible role in cytoskeleton regulation.…”

“…P53's interaction with Cdc42 inhibits both filo podia formation, cellular polarization and "in vitro" cellular spreading. Furthermore, Inhibition or absence of p53 leads to increased activity of the Rho pathway with consequent increase in cell migration [30].…”

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

“…Silencing of mutant p53 expression has no effect on cell migration, which is consistent with previous reports showing that silencing of endogenous mutant p53 expression alone does not alter cellular migration in the MDA-MB-231 breast cancer cell line (Adorno et al, 2009). However, expression of wild-type p53 has been demonstrated to inhibit cell migration (Gadea et al, 2002;Roger et al, 2006). Therefore, the observation that stable ANKRD11 expression can decrease the rate of cell migration in a mutant p53-dependent manner is likely due to a restoration of wild-type-like activity to the endogenous p53 mutant, as described previously (Neilsen et al, 2008).…”

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

“…In recent years, the idea has been increasingly put forth that p53 may suppress tumorigenesis through direct regulation of cell motility (reviewed in ref. 27). Interestingly, the other members of the p53 family, p63 and p73, have also been associated with having direct roles in regulating the expression of genes associated with cell motility.…”