title: CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation.
abstract: Caspase 8/10-associated RING proteins (CARPs) are a recently described family of protein ubiquitin ligases that interact with and negatively regulate death receptor-mediated apoptosis. Because CARPs are overexpressed in cancer and their silencing reduces cell viability and sensitizes tumor cells to chemotherapeutic agents, we investigated their relationship to p53 tumor suppressor signaling. p53 is a major determinant of chemosensitivity, and its levels are increased following DNA damage through N-terminal phosphorylation and inhibition of degradation. Although p53 is well known to be negatively regulated by several ubiquitin ligases including MDM2, none are known to target phosphorylated p53 for degradation. CARPs physically interact with and ubiquitinate p53, targeting it for degradation in the absence of MDM2. Serine 20-phosphorylated p53 is also ubiquitinated by CARPs. CARP silencing stimulates p53 expression and promotes downstream effects, including transcriptional activation and tumor suppression.
authors.affiliation: Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine, The Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, PA 19104, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yang
authors.forename: Laura M
authors.initials: LM
authors.lastname: Rozan
authors.forename: E Robert
authors.initials: ER
authors.lastname: McDonald
authors.forename: Arunasalam
authors.initials: A
authors.lastname: Navaraj
authors.forename: Jue Judy
authors.initials: JJ
authors.lastname: Liu
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Matthew
authors.forename: Wenge
authors.initials: W
authors.lastname: Wang
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases