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Cell. 2015 Apr 9;161(2):333-47. doi: 10.1016/j.cell.2015.03.001.

KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 p105 to p50 restricts tumor growth.

Author information

1
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.
2
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
3
Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
4
The Smoler Proteomics Center, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
5
Department of Pathology, Rambam Health Care Campus, Haifa 31096, Israel.
6
Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheba 84105, Israel.
7
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.
8
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.
9
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.
10
Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Haifa 34367, Israel.
11
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.

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.

PMID:
25860612
DOI:
10.1016/j.cell.2015.03.001
[Indexed for MEDLINE]
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