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

Yelena Kravtsova-Ivantsiv1, Inna Shomer1, Victoria Cohen-Kaplan1

  • 1The 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.

Cell
|April 11, 2015
PubMed

Insights

Researchers identified KPC1 as the ubiquitin ligase regulating NF-κB1 processing. This finding reveals a new mechanism controlling cell growth and tumor suppression by balancing transcription factor activity.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Nuclear factor kappa B (NF-κB) is a critical transcription factor regulating inflammation, cell proliferation, survival, and transformation.
  • The ubiquitin (Ub) system plays a key role in mediating NF-κB activation steps.
  • The precise mechanism of NF-κB1 precursor p105 processing to the active p50 subunit by the proteasome remains uncharacterized.

Purpose of the Study:

  • To identify the ubiquitin ligase (E3) responsible for the processing of NF-κB1 precursor p105 to the p50 subunit.
  • To investigate the role of this E3 ligase in regulating NF-κB1 processing under basal and stimulated conditions.
  • To explore the implications of KPC1-mediated NF-κB1 processing in tumor growth and cell growth control.

Main Methods:

  • Protein-protein interaction studies to identify the E3 ligase binding to p105.
  • Ubiquitination assays to confirm the enzymatic activity of the identified E3 ligase on p105.
  • Overexpression studies in cell models to assess the impact on p105 processing, NF-κB subunit levels, and tumor growth.
  • Transcriptional analysis to evaluate gene expression changes associated with KPC1 activity.

Main Results:

  • KPC1 was identified as the ubiquitin ligase that binds to the ankyrin repeats domain of p105.
  • KPC1 ubiquitinates p105 and mediates its processing to p50 under both basal and signaling conditions.
  • Overexpression of KPC1 inhibited tumor growth, correlating with increased p50 generation and downregulation of p65.
  • Transcript analysis showed increased expression of tumor-suppressive genes.

Conclusions:

  • KPC1 is the E3 ubiquitin ligase that controls the processing of NF-κB1 precursor p105 to the active p50 subunit.
  • KPC1-mediated regulation of NF-κB1 processing influences the balance between p50-p50 homodimers and p50-p65 heterodimers.
  • This regulatory mechanism plays a significant role in controlling cell growth and exhibits tumor-suppressive functions.

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