The expanding universe of p53 targets

Abstract

The p53 tumour suppressor is modified through mutation or changes in expression in most cancers, leading to the altered regulation of hundreds of genes that are directly influenced by this sequence-specific transcription factor. Central to the p53 master regulatory network are the target response element (RE) sequences. The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific RE sequences, all of which contribute to the role that p53 has in the aetiology of cancer. This Review describes the identification and functionality of REs and highlights the inclusion of non-canonical REs that expand the universe of genes and regulation mechanisms in the p53 tumour suppressor network.

p53-family proteins and their regulators: hubs and spokes in tumor suppression

“…Therefore, a great deal of interest is focused on understanding how different sets of genes are regulated by p53-family proteins in a signal-and context-dependent manner. Promoter selection has an integral part in determining the response to p53 family members, and differences in the sequence and spacing of p53-binding sites, specific PTMs, together with the presence or absence of specific cofactors, all contribute to promoter selection and, in turn, cellular response (see Vousden and Prives 6 and Menendez et al 8 …”

“…For an update on the complexity of p53 activities and regulation, the reader is referred to specific recent reviews (e.g., Kruse and Gu 5 , Vousden and Prives 6 , Green and Kroemer, 7 and Menendez et al 8 ).…”

Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics

“…This was supported by findings of a correlation between the presence transcription factors located in close proximity within the target promoter, where the p53 was a half-site created by an infrequent single nucleotide polymorphism. [25][26][27] Neither p53 nor ER alone could significantly upregulate FLT1, but the combination resulted in synergistic activation. 24 We proposed that noncanonical p53 REs consisting of ½ or ¾ sites can expand the p53 target network providing for moderate or weak p53 responsiveness, but at the same time providing the opportunity of conditional, context-dependent transactivation.…”

“…24 We proposed that noncanonical p53 REs consisting of ½ or ¾ sites can expand the p53 target network providing for moderate or weak p53 responsiveness, but at the same time providing the opportunity of conditional, context-dependent transactivation. 5,25,27 Also, in the case of ERs the structural organization of the response element (ERE) has been shown to influence the binding affinity as well as the modulation of the expression of target genes. The consensus half-site ERE is considered the minimal target site for ERs, and other transcription factors as well as cofactors can promote binding and transcriptional modulation.…”

p53 integrates host defense and cell fate during bacterial pneumonia

“…Promoter regions (3000 to 1000 from transcription start site) were evaluated for potential NF-B-binding sites with the use of MatInspector Release professional 8.0.5 software (Genomatix Software GmbH) using the MatInspector family matrix V$NFKB with 0.85 Optimized matrix threshold. Promoter regions were also analyzed for potential p53-binding sites by first identifying putative sites with the use of p53scan (Smeenk et al, 2008) and then ranking these sites for predicted p53 responsivity using established p53 response element functionality rules (Menendez et al, 2009). …”