Mutations in the amino-terminal transactivation domain of the tumor-suppressor are mostly insertions or deletions and result in loss of full-length p53 expression. for tumor suppression because these amino-terminal mutations are found in the germ line leading to the Li-Fraumeni syndrome. occur in the DNA-binding domain and lead to its functional inactivation their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length Astilbin p53 expression but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47 we demonstrate it to be up-regulated in response to various stimuli and to contribute to cell death through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation which depends on the amino terminus and is required for recruitment of selective cofactors. Consistently cancers capable of expressing p47 had a better overall survival. Nonetheless retention of the apoptotic function appears insufficient for tumor suppression because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53’s apoptosis proficiency is dispensable for tumor suppression but could prognosticate better survival. Major efforts in cancer genome sequencing have confirmed that is the most mutated gene in human malignancies (1) highlighting its crucial role in guarding against cellular transformation. Most mutations in occur in the central DNA-binding domain (DBD) expectedly due to p53’s major function as transcription factor that controls the expression of a plethora of genes that regulate apoptosis senescence cell-cycle arrest and DNA repair (2 3 Mouse knock-in models that recapitulate human cancer-derived p53 mutations and mimic the Li-Fraumeni syndrome (LFS) have confirmed that these DBD mutations lead to loss-of Astilbin function (LOF) Rabbit Polyclonal to IRF-3. or in certain cases gain-of-novel oncogenic functions which Astilbin appears to be mutation-type specific (4-6). Moreover mutant p53 has been shown to result in dominant-negative effect over the remaining wild-type allele thereby inhibiting efficient transcriptional activation and hence therapeutic response (5 7 collectively highlighting the importance of mutations in the DBD in contributing to carcinogenesis and affecting therapeutic outcome. Mutations in other domains of p53 have also been noted albeit to a lesser extent. For example mutations in the carboxyl-terminal oligomerization domain and in particular the R337H residue have been noted to be prevalent in the Brazilian LFS patients giving rise to a variety of tumor types (8) and especially adrenocortical carcinomas in children (9). This particular mutation causes defects in tetramer formation leading to loss of function (10) thereby highlighting other possible avenues by which mutations can inactivate p53 functionally. Similarly mutations in the amino-terminal domain of p53 which contains the transactivation (TA) 1 and 2 domains within amino acid residues 1-40 and 41-61 respectively (11 12 have also been noted. This region of p53 contains several regulatory elements such as the MDM2 and p300 binding sites within the first 40 aa which regulates p53 stability through ubiquitination and activation through acetylation respectively (13 14 Furthermore it is to be noted that alternate translation initiation from the methionine in exon 4 Astilbin (at amino acids 40 or 44 of human p53) leads to the production of the amino-terminal truncated form termed as p47 (also referred to as p44 p53/p47 ΔΝp53 or Δ40p53) which lacks the TA1 (15-18). Thus p47 Astilbin was initially thought to lack the ability to transactivate targets genes and was indeed reported to lack the ability to induce apoptosis (15). However subsequent data has suggested that it is capable of inducing expression of some p53 target genes (16 19 Nonetheless whether the presence of mutations in the amino terminus especially in the region between the first two methionines (i.e. amino acids 1-40) (referred hereafter as ATp53 mutations) could affect the structure and functionality of p53 is unclear. Whereas not much information is available on the.