title: TAp73 promotes cell survival upon genotoxic stress by inhibiting p53 activity.
abstract: p53 plays a key role in regulating DNA damage response by suppressing cell cycle progression or inducing apoptosis depending on extent of DNA damage. However, it is not clear why mild genotoxic stress favors growth arrest, whereas excessive lesions signal cells to die. Here we showed that TAp73, a p53 homologue thought to have a similar function as p53, restrains the transcriptional activity of p53 and prevents excessive activation of its downstream targets upon low levels of DNA damage, which results in cell cycle arrest. Extensive DNA damage triggers TAp73 depletion through ubiquitin/proteasome-mediated degradation of E2F1, leading to enhanced transcriptional activation by p53 and subsequent induction of apoptosis. These findings provide novel insights into the regulation of p53 function and suggest that TAp73 keeps p53 activity in check in regulating cell fate decisions upon genotoxic stress.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Dongshi
authors.initials: D
authors.lastname: Chen
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ming
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. College of Life Sciences, Sichuan University, Chengdu, Sichuan, 610064, P.R. China.
authors.forename: Fangdong
authors.initials: F
authors.lastname: Zou
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Peng
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D046988:Proteasome Endopeptidase Complex