title: A rare DNA contact mutation in cancer confers p53 gain-of-function and tumor cell survival via TNFAIP8 induction.
abstract: The p53 tumor suppressor gene encodes a sequence-specific transcription factor. Mutations in the coding sequence of p53 occur frequently in human cancer and often result in single amino acid substitutions (missense mutations) in the DNA binding domain (DBD), blocking normal tumor suppressive functions. In addition to the loss of canonical functions, some missense mutations in p53 confer gain-of-function (GOF) activities to tumor cells. While many missense mutations in p53 cluster at six "hotspot" amino acids, the majority of mutations in human cancer occur elsewhere in the DBD and at a much lower frequency. We report here that mutations at K120, a non-hotspot DNA contact residue, confer p53 with the previously unrecognized ability to bind and activate the transcription of the pro-survival TNFAIP8 gene. Mutant K120 p53 binds the TNFAIP8 locus at a cryptic p53 response element that is not occupied by wild-type p53. Furthermore, induction of TNFAIP8 is critical for the evasion of apoptosis by tumor cells expressing the K120R variant of p53. These findings identify induction of pro-survival targets as a mechanism of gain-of-function activity for mutant p53 and will likely broaden our understanding of this phenomenon beyond the limited number of GOF activities currently reported for hotspot mutants.
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, United States. Electronic address: monteith.jessica@gmail.com.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Monteith
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, United States. Electronic address: hestiamellert@gmail.com.
authors.forename: Hestia
authors.initials: H
authors.lastname: Mellert
authors.affiliation: Cell and Developmental Biology, Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, 9-125 Smilow Center for Translational Research, Philadelphia, PA 19104, United States. Electronic address: msammons@mail.med.upenn.edu.
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Sammons
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, United States; University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States. Electronic address: laudita.kuswanto@utsouthwestern.edu.
authors.forename: Laudita A
authors.initials: LA
authors.lastname: Kuswanto
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, United States; Medical Genetics and Molecular Biology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States. Electronic address: Stephen.sykes@fccc.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Resnick-Silverman
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: james.manfredi@mssm.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Manfredi
authors.affiliation: Cell and Developmental Biology, Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, 9-125 Smilow Center for Translational Research, Philadelphia, PA 19104, United States. Electronic address: berger@upenn.edu.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, United States. Electronic address: Steven.mcmahon@jefferson.edu.
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004247:DNA / Q000235:genetics*; D056426:Genetic Loci; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D059372:Nucleotide Motifs / Q000235:genetics; D011485:Protein Binding; D015203:Reproducibility of Results; D020218:Response Elements / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C404190:TNFAIP8 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA
keywords: Gain of function; Mutant p53; Pro-survival; TNFα