294097.fig.004a
(a)
294097.fig.004b
(b)
Figure 4: Regulation of metastasis by mutant p53 and Smads. (a) p63 has a crucial role in the transcriptional activation of genes which function in the inhibition of metastasis. Mutant p53 can act to inhibit the anti-metastatic functioning of p63 but is dependent upon the formation of a ternary complex with Smads2/3 as described below [53]. Formation of a ternary complex inhibits the binding of p63 to the DNA at target gene promoters thereby inhibiting transcription of these key antimetastatic genes and subsequently increased metastasis of malignant cells is observed [53]. In addition mutant p53 can promote invasion and metastasis independently. For example mutant p53 can suppress p63 in the context of integrin recycling [54]. It is yet unknown whether Smads are involved for these other routes of induction. (b) Mutant p53 is able to inhibit p63 activity by the formation of a ternary complex. Formation of this complex is dependent on receptor Smad2/3 acting as a molecular bridge between the proteins. The C-terminal MH1 domain of Smads2/3 binds the transactivational (TA) domain at the N-terminus of mutant p53 [53]. The N-terminal MH2 domain binds at the C-terminal alpha domain of p63 [53]. Association of p63 in this complex inhibits its capacity to bind DNA thus blocking transcriptional functions of the protein.