KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth

Yelena Kravtsova-Ivantsiv; Inna Shomer; Victoria Cohen-Kaplan; Berend Snijder; Giulio Superti-Furga; Hedva Gonen; Thomas Sommer; Tamar Ziv; Arie Admon; Inna Naroditsky; Muhammad Jbara; Ashraf Brik; Eli Pikarsky; Yong Tae Kwon; Ilana Doweck; Aaron Ciechanover

doi:10.1016/j.cell.2015.03.001

KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth

Yelena Kravtsova-Ivantsiv, Inna Shomer, Victoria Cohen-Kaplan, Berend Snijder, Giulio Superti-Furga, Hedva Gonen, Thomas Sommer, Tamar Ziv, Arie Admon, Inna Naroditsky, Muhammad Jbara, Ashraf Brik, Eli Pikarsky, Yong Tae Kwon, Ilana Doweck, Aaron Ciechanover^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	333-347
Number of pages	15
Journal	Cell
Volume	161
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2015.03.001
State	Published - 9 Apr 2015

Bibliographical note

Funding Information:
Research in the laboratory of A.C. is supported by grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation (ISF), the I-CORE Program of the Planning and Budgeting Committee and the ISF (Grant1775/12), the EU Treat PolyQ Network, the Nobel Laureates Invitation Program of Seoul National University, the Deutsch-Israelische Projektkooperation (DIP), and the Program for Targeting Cancer by Modulating Protein Dynamics supported by Albert Sweet (Malibu, CA). We thank Dr. Kazuhiro Iwai (Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan) for providing us with some cDNAs. RNA-seq and mapping to the human genome was done by the Technion Genome Center. B.S. is supported by a fellowship from the Swiss National Science Foundation. Y.T.K. is supported by The Basic Science Research Programs of the National Research Foundation of Korea (NRF-2013R1A2A2A01014170). A.C. is an Israel Cancer Research Fund (ICRF) USA Professor.

Publisher Copyright:
© 2015 Elsevier Inc.

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Kravtsova-Ivantsiv, Y., Shomer, I., Cohen-Kaplan, V., Snijder, B., Superti-Furga, G., Gonen, H., Sommer, T., Ziv, T., Admon, A., Naroditsky, I., Jbara, M., Brik, A., Pikarsky, E., Kwon, Y. T., Doweck, I., & Ciechanover, A. (2015). KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth. Cell, 161(2), 333-347. https://doi.org/10.1016/j.cell.2015.03.001

@article{96609f9ddada42f8ad293c54488aca36,

title = "KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth",

abstract = "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.",

author = "Yelena Kravtsova-Ivantsiv and Inna Shomer and Victoria Cohen-Kaplan and Berend Snijder and Giulio Superti-Furga and Hedva Gonen and Thomas Sommer and Tamar Ziv and Arie Admon and Inna Naroditsky and Muhammad Jbara and Ashraf Brik and Eli Pikarsky and Kwon, {Yong Tae} and Ilana Doweck and Aaron Ciechanover",

note = "Funding Information: Research in the laboratory of A.C. is supported by grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation (ISF), the I-CORE Program of the Planning and Budgeting Committee and the ISF (Grant1775/12), the EU Treat PolyQ Network, the Nobel Laureates Invitation Program of Seoul National University, the Deutsch-Israelische Projektkooperation (DIP), and the Program for Targeting Cancer by Modulating Protein Dynamics supported by Albert Sweet (Malibu, CA). We thank Dr. Kazuhiro Iwai (Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan) for providing us with some cDNAs. RNA-seq and mapping to the human genome was done by the Technion Genome Center. B.S. is supported by a fellowship from the Swiss National Science Foundation. Y.T.K. is supported by The Basic Science Research Programs of the National Research Foundation of Korea (NRF-2013R1A2A2A01014170). A.C. is an Israel Cancer Research Fund (ICRF) USA Professor. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = apr,

day = "9",

doi = "10.1016/j.cell.2015.03.001",

language = "American English",

volume = "161",

pages = "333--347",

journal = "Cell",

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Kravtsova-Ivantsiv, Y, Shomer, I, Cohen-Kaplan, V, Snijder, B, Superti-Furga, G, Gonen, H, Sommer, T, Ziv, T, Admon, A, Naroditsky, I, Jbara, M, Brik, A, Pikarsky, E, Kwon, YT, Doweck, I & Ciechanover, A 2015, 'KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth', Cell, vol. 161, no. 2, pp. 333-347. https://doi.org/10.1016/j.cell.2015.03.001

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 - Funding Information: Research in the laboratory of A.C. is supported by grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation (ISF), the I-CORE Program of the Planning and Budgeting Committee and the ISF (Grant1775/12), the EU Treat PolyQ Network, the Nobel Laureates Invitation Program of Seoul National University, the Deutsch-Israelische Projektkooperation (DIP), and the Program for Targeting Cancer by Modulating Protein Dynamics supported by Albert Sweet (Malibu, CA). We thank Dr. Kazuhiro Iwai (Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan) for providing us with some cDNAs. RNA-seq and mapping to the human genome was done by the Technion Genome Center. B.S. is supported by a fellowship from the Swiss National Science Foundation. Y.T.K. is supported by The Basic Science Research Programs of the National Research Foundation of Korea (NRF-2013R1A2A2A01014170). A.C. is an Israel Cancer Research Fund (ICRF) USA Professor. 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.

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U2 - 10.1016/j.cell.2015.03.001

DO - 10.1016/j.cell.2015.03.001

M3 - Article

C2 - 25860612

AN - SCOPUS:84927154859

SN - 0092-8674

VL - 161

SP - 333

EP - 347

JO - Cell

JF - Cell

IS - 2

ER -

KPC1-mediated ubiquitination and proteasomal processing of nf-κb1 p105 to p50 restricts tumor growth

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