ArticleProceedings of the National Academy of Sciences of the United States of America2020
Excess of the NF-ĸB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1- and chemokines-mediated mechanisms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.Nature communications · 2026Article
- Negative regulation of the NF-κB pathway by the ubiquitin ligase Nedd4-1(NE).Communications biology · 2026Article
- Augment proteasome inhibitor efficacy activates CD8Cell reports. Medicine · 2025Article
- CXCL12 restricts tumor growth by suppressing the Ras, ERK1/2, c-Myc, and the immune checkpoint PD-L1 pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Ubiquitin modification in the regulation of tumor immunotherapy resistance mechanisms and potential therapeutic targets.Experimental hematology & oncology · 2024Review
- The Immunomodulatory Effects of Sulforaphane in Exercise-Induced Inflammation and Oxidative Stress: A Prospective Nutraceutical.International journal of molecular sciences · 2024Review
- The ubiquitin-proteasome system in the tumor immune microenvironment: a key force in combination therapy.Frontiers in immunology · 2024Review
- Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages inInternational journal of biological sciences · 2024Article
- Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis.Journal for immunotherapy of cancer · 2023Article
- circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells.Cellular and molecular life sciences : CMLS · 2023Article
- The NF-ĸB p50 subunit generated by KPC1-mediated ubiquitination and limited proteasomal processing, suppresses tumor growth.Cancer cell international · 2023Review
- Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies.BMC medicine · 2022Article
- Panels of mRNAs and miRNAs for decoding molecular mechanisms of Renal Cell Carcinoma (RCC) subtypes utilizing Artificial Intelligence approaches.Scientific reports · 2022Article
- Emodin alleviates sepsis-mediated lung injury via inhibition and reduction of NF-kB and HMGB1 pathways mediated by SIRT1.The Kaohsiung journal of medical sciences · 2022Article
- A short binding site in the KPC1 ubiquitin ligase mediates processing of NF-κB1 p105 to p50: A potential for a tumor-suppressive PROTAC.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies.Discover oncology · 2021Review
- Anticancer Targets and Signaling Pathways Activated by Britannin and Related Pseudoguaianolide Sesquiterpene Lactones.Biomedicines · 2021Review
- Transcription Coactivator BCL3 Acts as a Potential Regulator of Lipid Metabolism Through the Effects on Inflammation.Journal of inflammation research · 2021Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
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Abstract
Nuclear factor-ĸB (NF-ĸB) transcription factor is a family of essential regulators of the immune response and cell proliferation and transformation. A typical factor is a heterodimer made of either p50 or p52, which are limited processing products of either p105 or p100, respectively, and a member of the Rel family of proteins, typically p65. The transcriptional program of NF-ĸB is tightly regulated by the composition of the dimers. In our previous work, we demonstrated that the ubiquitin ligase KPC1 is involved in ubiquitination and proteasomal processing of p105 to generate p50. Its overexpression and the resulting high level of p50 stimulates transcription of a broad array of tumor suppressors. Here we demonstrate that additional mechanisms are involved in the p50-mediated tumor-suppressive effect. p50 down-regulates expression of a major immune checkpoint inhibitor, the programmed cell death-ligand 1 (PD-L1), both in cells and in tumors. Importantly, the suppression is abrogated by overexpression of p65. This highlights the importance of the cellular quantities of the two different subunits of NF-ĸB which determine the composition of the dimer. While the putative p50 homodimer is tumor-suppressive, the "canonical" p50p65 heterodimer is oncogenic. We found that an additional mechanism is involved in the tumor-suppressive phenomenon: p50 up-regulates expression of the proinflammatory chemokines CCL3, CCL4, and CCL5, which in turn recruit into the tumors active natural killer (NK) cells and macrophages. Overall, p50 acts as a strong tumor suppressor via multiple mechanisms, including overexpression of tumor suppressors and modulation of the tumor microenvironment by recruiting active immune cells.
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