P53 regulation through the Nterminal transactivation domain

Posttranslational modifications result in confor-mational changes within the p53 molecule and hence activation of p53. These modifications include p53 regulation through phosphory-lation sites in the N-terminal transactivation domain (residues 1-44) (Figure 12.2). While the phosphorylation sites have not yet been fully characterized, serine (Ser) 4, Ser6 and Ser9 for the casein kinase (CK) I site, and Ser 15 and Ser37 for the DNA-protein kinase (PK) site appear to be important.9

The interaction of the N-terminal domain of p53 with other proteins within the transcrip-tional machinery is pivotal to its role as a tran-scriptional activator. p53-interacting proteins belonging to the transcription machinery include MDM-2, the DNA sequence of Ts and As where transcription factors bind (TATA) box-binding protein (TBP), TBP-associated factor (TAF), the p62 component of transcription factor IIH (TFIIH) and p300/CPB (CREB Binding Protein).15 Amongst the key p53 N-terminal-interacting proteins, in which altered expression is demonstrated in many cancers -including breast cancer - is the MDM-2 protein.22 MDM-2 controls the biological activity of p53 and targets p53 for destruction, acting as an E3 ligase to conjugate ubiquitin to p53, which provides a signal for p53 to be degraded by the proteasome. MDM-2 is a target gene of p53 and is therefore upregulated when p53 is activated, thus providing an inbuilt negativefeedback loop mechanism whereby p53 expression is controlled at the cellular level. The p53-MDM-2 protein interaction is of physiological relevance, as evidenced by overexpression of MDM-2 protein inactivating wild-type p53 in soft tissue sarcomas.23 In addition, early embryonic lethal phenotype of an MDM-2 knockout mouse is rescued when crossed into a p53 null phenotype.24

Changes within the N-terminal domain, through interactions with other proteins, can quantitatively increase DNA binding, whereas the opposite is true for changes brought about through phosphorylation of the N-terminal sites in p53.8 Posttranslational modification of the p53 N-terminus at Ser15 by DNA-PK has been shown to reduce the ability of p53 and MDM-2 to bind, and since MDM-2 is a strong promoter of p53 degradation this results in p53 stabilization and hence accumulation.8 The role of MDM-2 in p53 protein stabilization is further supported by the fact that the tumor suppressor p19ARF (alternating reading frame spliced product of the murine p16INK4A locus) induces p53 stabilization through its interaction with MDM-2.

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