%0 Journal Article
%T ¦¤Np63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation
%A Ashley L Craig
%A Jitka Holcakova
%A Lee E Finlan
%A Marta Nekulova
%A Roman Hrstka
%A Nuri Gueven
%A James DiRenzo
%A Graeme Smith
%A Ted R Hupp
%A Borivoj Vojtesek
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-195
%X We now report that phosphorylation of the p53 tumour suppressor is positively regulated by ¦¤Np63¦Á in immortalised human keratinocytes. ¦¤Np63¦Á depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of ¦¤Np63¦Á in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct ¦¤Np63¦Á transcriptional target and that the ¦¤Np63¦Á response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the ¦¤Np63-specific TA2 transactivation domain mediates ATM transcription in coordination with the DNA binding and SAM domains.Germline p63 point mutations are associated with a range of ectodermal developmental disorders, and targeted p63 deletion in the skin causes premature ageing. The ¦¤Np63¦Á-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.p63 is the founding member of the p53 protein family, and is required for the development of limbs and epithelial structures in vertebrates [1]. The p63 gene expresses at least 6 common transcripts by utilising two distinct promoters (TA and ¦¤N) and alternative splicing within the 3' end of mRNA that generates ¦Á,¦Â and ¦Ã isoforms [2]. TAp63 variants contain a p53-like TA1 transactivation domain. ¦¤Np63 variants lack a TA1 domain, but instead contain a unique 14 amino acid sequence that contributes to the formation of an alternative TA2 transactivation domain [3]. All p63 variants contain a DNA-binding domain and a tetramerisation domain with homology to p53. However, p63 alpha isoforms encode a C-terminal extension containing a SAM protein interaction domain, a conserved functional element found in a range of developmental proteins [4].Initial studies identified p63 as a robust biomarker for epithelial progenitor, or stem, cells [5]. However, the development of TA- and ¦¤N-isotype specific reagents r
%U http://www.molecular-cancer.com/content/9/1/195