Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis

Significance Mutations in the amino-terminal transactivation domain of the tumor-suppressor p53 are mostly insertions or deletions, and result in loss of full-length p53 expression. However, these changes concomitantly result in the expression of a truncated p47 isoform, which retains the ability to selectively transactivate some apoptotic target genes. The selectivity appears to be due to a default feature, stemming from the lack of acetylation on K382 at the carboxyl terminus, which requires the amino terminus. Consistently, expression of p47 could prognosticate better survival in sporadic cancer patients, corroborating with its ability to induce apoptosis. However, apoptosis proficiency appears to be insufficient for tumor suppression, because these amino-terminal mutations are found in the germ line, leading to the Li–Fraumeni syndrome. Whereas most mutations in p53 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 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.

[1]  F. McKeon,et al.  Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome , 2015, Nature Cell Biology.

[2]  Mingming Jia,et al.  COSMIC: exploring the world's knowledge of somatic mutations in human cancer , 2014, Nucleic Acids Res..

[3]  K. Sabapathy,et al.  Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs , 2014, Cell Death and Differentiation.

[4]  G. Lozano,et al.  The mutant p53 mouse as a pre-clinical model , 2013, Oncogene.

[5]  A. Strasser,et al.  p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. , 2013, Cell reports.

[6]  V. Gorgoulis,et al.  PIG3: a novel link between oxidative stress and DNA damage response in cancer. , 2012, Cancer letters.

[7]  Ming K. Lee,et al.  Cell-type, dose, and mutation-type specificity dictate mutant p53 functions in vivo. , 2012, Cancer cell.

[8]  Carol Prives,et al.  Mutant p53: one name, many proteins. , 2012, Genes & development.

[9]  Wei Gu,et al.  Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence , 2012, Cell.

[10]  R. Zeillinger,et al.  The N-Terminally Truncated p53 Isoform &Dgr;40p53 Influences Prognosis in Mucinous Ovarian Cancer , 2012, International Journal of Gynecologic Cancer.

[11]  M. Scott,et al.  Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages , 2011, Proceedings of the National Academy of Sciences.

[12]  A. Strasser,et al.  Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases , 2011, The EMBO journal.

[13]  M. Mclaughlin,et al.  Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression , 2011, Cell.

[14]  L. Attardi,et al.  In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models. , 2010, Carcinogenesis.

[15]  R. Elkon,et al.  BRD7 is a candidate tumour suppressor gene required for p53 function , 2010, Nature Cell Biology.

[16]  Y. Xu,et al.  A common gain of function of p53 cancer mutants in inducing genetic instability , 2010, Oncogene.

[17]  Thomas Downey,et al.  A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics , 2010, Clinical & Experimental Metastasis.

[18]  K. Kinzler,et al.  A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53 , 2009, Proceedings of the National Academy of Sciences.

[19]  M. Olivier,et al.  Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. , 2008, Cancer letters.

[20]  Xin Cai,et al.  An acetylation switch in p53 mediates holo-TFIID recruitment. , 2007, Molecular cell.

[21]  Donald Bashford,et al.  A fluid salt-bridging cluster and the stabilization of p53. , 2007, Journal of molecular biology.

[22]  C. Prives,et al.  hCAS/CSE1L Associates with Chromatin and Regulates Expression of Select p53 Target Genes , 2007, Cell.

[23]  M. Olivier,et al.  Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database , 2007, Human mutation.

[24]  A. Fersht,et al.  Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53 , 2007, Proceedings of the National Academy of Sciences.

[25]  Ming K. Lee,et al.  Cancer-derived p53 mutants suppress p53-target gene expression—potential mechanism for gain of function of mutant p53 , 2007, Nucleic acids research.

[26]  Y. Taya,et al.  Dissecting functional roles of p53 N‐terminal transactivation domains by microarray expression analysis , 2007, Cancer science.

[27]  R. Fåhraeus,et al.  Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation , 2006, Oncogene.

[28]  R. Grover,et al.  Two internal ribosome entry sites mediate the translation of p53 isoforms , 2006, EMBO reports.

[29]  M. de Castro,et al.  Inheritance of R337H p53 gene mutation in children with sporadic adrenocortical tumor. , 2005, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[30]  G. Matlashewski,et al.  Regulation of Human p53 Activity and Cell Localization by Alternative Splicing , 2004, Molecular and Cellular Biology.

[31]  P. Hainaut,et al.  ΔN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53 , 2002, Oncogene.

[32]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[33]  Yili Yin,et al.  p53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products , 2002, Nature Cell Biology.

[34]  Kozo Nakamura,et al.  p53AIP1 regulates the mitochondrial apoptotic pathway. , 2002, Cancer research.

[35]  M. Blagosklonny,et al.  p53 from complexity to simplicity: mutant p53 stabilization, gain‐of‐function, and dominant‐negative effect , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  Yusuke Nakamura,et al.  p53AIP1, a Potential Mediator of p53-Dependent Apoptosis, and Its Regulation by Ser-46-Phosphorylated p53 , 2000, Cell.

[37]  S. Berger,et al.  Two tandem and independent sub-activation domains in the amino terminus of p53 require the adaptor complex for activity , 1997, Oncogene.

[38]  A. Levine,et al.  Identification of a novel p53 functional domain that is necessary for efficient growth suppression. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[40]  P. Hainaut,et al.  DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. , 2002, Oncogene.

[41]  I. Yin.  Corrigendum: p53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products , 2002, Nature Cell Biology.