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KPC1-mediated ubiquitination and proteasomal processing of NF-{kappa}B1 p105 to p50 restricts tumor growth

Item Type:Article
Title:KPC1-mediated ubiquitination and proteasomal processing of NF-{kappa}B1 p105 to p50 restricts tumor growth
Creators Name:Kravtsova-Ivantsiv, Y. and Shomer, I. and Cohen-Kaplan, V. and Snijder, B. and Superti-Furga, G. and Gonen, H. and Sommer, T. and Ziv, T. and Admon, A. and Naroditsky, I. and Jbara, M. and Brik, A. and Pikarsky, E. and Kwon, Y.T. and Doweck, I. and Ciechanover, A.
Abstract:NF-{kappa}B 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-{kappa}B1 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-{kappa}B1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.
Keywords:Amino Acid Sequence, Cell-Free System, Intracellular Signaling Peptides and Proteins, NF-{kappa} B p50 Subunit, Neoplasms, Proteasome Endopeptidase Complex, Sequence Alignment, Signal Transduction, Tertiary Protein Structure, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Source:Cell
ISSN:0092-8674
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:161
Number:2
Page Range:333-347
Date:9 April 2015
Official Publication:https://doi.org/10.1016/j.cell.2015.03.001
PubMed:View item in PubMed

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