title: CARPs are E3 ligases that target apical caspases and p53.
abstract: Apoptosis is mediated by executioner caspases that are negatively regulated by the inhibitors of apoptosis (IAPs). Apical or initiator caspases are not the substrates of IAPs for degradation or sequestration. Newly characterized proteins, caspases-8/10 associated RING proteins 1 and 2 (CARP1/2) exhibit significant similarity to classical inhibitors of apoptosis (IAPs) in both structure and function, however the diverse substrate specificity of CARPs distinguishes them from the family of IAPs. CARPs, act as RING-domain E3 ligases, ubiquitinate apical caspases and target them for proteasome-mediated degradation. CARP inhibition of apoptotic signaling in the extrinsic cell death pathway is released by caspase-dependent cleavage. Besides the features in common between CARPs and IAPs, CARPs contain a FYVE domain that can serve as a membrane-targeting or endosome localizing signal. CARP gene silencing inhibits tumor cell survival and increases cancer cell sensitivity to the death ligand or chemotherapy-induced apoptosis. CARP proteins, which are overexpressed in cancer, target the tumor suppressor p53 for degradation. Unlike other E3 ligases that target p53, CARPs are capable of ubiquitinating DNA damage-induced phospho-p53 at serine 15 or 20, adding a new layer of regulation of cellular apoptosis and suggesting a novel target for therapeutic intervention.
authors.affiliation: Departments of Medicine (Hematology/Oncology), Genetics and Pharmacology, The Institute for Translational Medicine and Therapeutics, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yang
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D018797:Cell Cycle Proteins; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C512817:CA11 protein, human; C477529:CCAR1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases