TY - JOUR
T1 - KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth
AU - Kravtsova-Ivantsiv, Yelena
AU - Shomer, Inna
AU - Cohen-Kaplan, Victoria
AU - Snijder, Berend
AU - Superti-Furga, Giulio
AU - Gonen, Hedva
AU - Sommer, Thomas
AU - Ziv, Tamar
AU - Admon, Arie
AU - Naroditsky, Inna
AU - Jbara, Muhammad
AU - Brik, Ashraf
AU - Pikarsky, Eli
AU - Kwon, Yong Tae
AU - Doweck, Ilana
AU - Ciechanover, Aaron
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/4/9
Y1 - 2015/4/9
N2 - Summary 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.
AB - Summary 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.
UR - http://www.scopus.com/inward/record.url?scp=84927154859&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.03.001
DO - 10.1016/j.cell.2015.03.001
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C2 - 25860612
AN - SCOPUS:84927154859
SN - 0092-8674
VL - 161
SP - 333
EP - 347
JO - Cell
JF - Cell
IS - 2
ER -