title: KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 p105 to p50 restricts tumor growth.
abstract: NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.
authors: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors: Yelena
authors: Y
authors: Kravtsova-Ivantsiv
authors: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors: Inna
authors: I
authors: Shomer
authors: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors: Victoria
authors: V
authors: Cohen-Kaplan
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors: Berend
authors: B
authors: Snijder
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors: Giulio
authors: G
authors: Superti-Furga
authors: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors: Hedva
authors: H
authors: Gonen
authors: Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors: Thomas
authors: T
authors: Sommer
authors: The Smoler Proteomics Center, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors: Tamar
authors: T
authors: Ziv
authors: The Smoler Proteomics Center, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors: Arie
authors: A
authors: Admon
authors: Department of Pathology, Rambam Health Care Campus, Haifa 31096, Israel.
authors: Inna
authors: I
authors: Naroditsky
authors: Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheba 84105, Israel.
authors: Muhammad
authors: M
authors: Jbara
authors: Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheba 84105, Israel; The Schulich Faculty of Chemistry, Technion Israel Institute of Technology, Haifa 32000, Israel.
authors: Ashraf
authors: A
authors: Brik
authors: Department of Immunology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Institute for Medical Research Israel-Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Eli
authors: E
authors: Pikarsky
authors: Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul 110-799, South Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, South Korea.
authors: Yong Tae
authors: YT
authors: Kwon
authors: Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Haifa 34367, Israel.
authors: Ilana
authors: I
authors: Doweck
authors: The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel; Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul 110-799, South Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, South Korea. Electronic address: aaroncie@tx.technion.ac.il.
authors: Aaron
authors: A
authors: Ciechanover
mesh_terms: D000595:Amino Acid Sequence; D002474:Cell-Free System; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D052002:NF-kappa B p50 Subunit / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000302:isolation & purification / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D025521:Tumor Suppressor Proteins; C574376:RNF123 protein, human; C412480:UBAC1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex