Schematic representation of changes in morphology caused by the p53 deficiency in mouse embryonic fibroblasts. Loss of p53 activity results in rounded blebbing movement (right).

The role of p53 in controlling cell-cycle arrest and apoptosis has been well-characterised but the tumour suppressor has more recently been linked with cell morphology. Published in The Journal of Cell Biology, Roux and colleagues report that p53 affects cell migration morphology by controlling localisation of the key cytoskeletal regulator RhoA, leading to an increase in cell invasiveness.

Tumour progression is characterised by two major steps; uncontrolled cell proliferation, followed by migration away from the primary tumour site to form metastases. A tumour cell's capacity for invading adjacent tissue is linked to morphological modifications; cells with a more rounded morphology often show increased migration.

Roux and colleagues studied how p53 affects the morphology and migration properties of mouse embryonic fibroblasts (MEFs) cultured in a 3D matrigel that approximates the in vivo environment. Upon loss of p53 activity, cells shifted from an elongated shape to a more rounded one, characterised by highly dynamic membrane blebs, a greater number of peripheral filopodia and a sixfold increase in migration speed.

How does p53 control the change in morphology and motility? One candidate target is the Rho GTPases, which control cell migration by affecting adhesion and the actin cytoskeleton. RhoA and its effector Rho kinase (ROCK) are known to affect focal adhesion and actin stress fibre formation, and are also implicated in round bleb-associated motility. Roux and colleagues found increased levels of active GTP-bound RhoA in MEFs lacking p53. Both RhoA and actin stress fibres were redistributed to bleb-like globular protrusions and filopodia at the cell surface, but were lost from perinuclear regions. Inactivation of RhoA abolished these bleb-like structures, suggesting that RhoA activation is required for bleb formation in p53^-/- cells. Inhibition of ROCK in cells lacking p53 also resulted in the loss of dynamic bleb-like activity and triggered a change in morphology from rounded to flattened. Furthermore, these inhibitors reduced the number of stress fibres and initiated relocalisation of RhoA to the perinuclear region. Thus, p53 modulates cell migration by controlling RhoA localization and regulating the RhoA-ROCK signalling pathway. Loss of p53 results in the aberrant overactivation of RhoA and ROCK-dependent translocation of RhoA to membrane blebbing structures.

Both MEFs and cancer cells were more invasive in the absence of p53. Like MEFs, melanoma cells switched to a rounded blebbing morphology upon expression of dominant-negative p53 — an effect that required RhoA — which also increased their invasive potential in 3D matrices. p53 loss-of-function mutations can be found in over 50% of human cancers. As p53 affects the two main stages of tumour progression — cell proliferation and cell invasion — anti-cancer agents aimed at restoring p53 function may be both anti-proliferative and anti-invasive.

Author: Kim Baumann