Figure 2: Coregulation of gene transcription by p53 and Smad complexes. In the absence of cellular stress p53 is maintained at a low concentration by its negative regulator MDM2 [27, 28, 45]. MDM2 acts to poly-ubiquitinate p53, which targets the tumour suppressor to the proteasome for degradation. In response to DNA damage p53 is phosphorylated at defined Ser/Thr residues resulting in its stabilisation and dissociation from MDM2 [29]. In addition signalling via the Ras/MAPK pathway CK1δ/ε can also result in the activating phosphorylation of p53 [46]. Activated wild-type p53 can act synergistically with Smads to increase the transcription of a subset of genes for example, p21, PAI-1 [46, 47]. The model depicted was originally proposed by Piccolo and colleagues and elegantly demonstrates how p53 and Smads may interact [4648]. For synergism to occur, the target gene must possess both a DNA-SBE and a p53 response element (RE) to which the activated Smad complex and p53 bind respectively. Once bound at their respective sequences a direct interaction between Smads and p53 may occur in which the N-terminal MH1 domain of Smads2/3 binds the N-terminal transactivational domain (TA) of p53 [4648]. Association within the gene promoter acts to maximally induce gene transcription.