p53 and its mutants in tumor cell migration and invasion

Abstract

In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function.

Figure 1.

p53 opposes EMT and cell migration to prevent metastasis. p53 plays a role in opposing EMT and cell migration. A hallmark of EMT is loss of E-cadherin, and p53 can prevent this by inhibiting Slug or the adhesion molecule EpCam expression. Furthermore, loss of p53 or decreased p53 activity after Twist expression can therefore drive EMT. p53 can also inhibit invasive migration. This can be mediated via increased expression of Caldesmon or miRNA-143 to oppose invadopodia formation. By transactivating PTEN, p53 can reduce PIP3 (and thereby Rac) levels, resulting in inhibition of mesenchymal/elongated motility. p53 can also inhibit amoeboid cell motility by preventing activation of ROCK, either by inducing Notch or by promoting RhoE (Rnd3)-mediated inhibition of RhoA. E-CAD, E-cadherin.

Figure 2.

Mutant p53 regulates cell migration and invasion by inhibiting p63. (A) Upon TGF-β induction, SMAD2 is phosphorylated and promotes binding of mutant p53 to p63, alleviating p63-mediated suppression of Sharp-1 and Cyclin G2 to allow for cell migration and invasion. (B) p63 inhibits activation of RCP (through transcriptional targets that are currently unknown) to prevent α5β1 integrin and EGFR recycling to the plasma membrane. Upon expression of mutant p53, p63 activity is suppressed, resulting in enhanced RCP-driven recycling of α5β1 integrin and EGFR. This activates Rho and PKB/Akt to promote cell migration and invasion.