ArticleHepatology (Baltimore, Md.)2015
NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer.
Article in Hepatology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 67 citations in OpenAlex.
- Retraction Note: p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs.Nature communications · 2026Article
- Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- NUMB in Endometrial Pathology: From Adenomyosis Expression Patterns to Endometrial Cancer Survival Implications.Current issues in molecular biology · 2025Article
- Breaking bottlenecks: the future of hepatocellular carcinoma clinical trials and therapeutic targets.Hepatology international · 2025Review
- LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53.Cell death & disease · 2025Article
- The CRL7Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Luciferase-Based Reporter Assay for the Assessment of Aurora A-Kinase Activity in Mitotic Cycle.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Integrating Physical and Biochemical Cues for Muscle Engineering: Scaffolds and Graft Durability.Bioengineering (Basel, Switzerland) · 2024Review
- Promotion of nerve regeneration and motor function recovery in SCI rats using LOCAS-iPSCs-NSCs.Stem cell research & therapy · 2024Article
- NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells.Experimental & molecular medicine · 2024Article
- MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells.Cell death discovery · 2023Article
- Review
- KCTD10 functions as a tumor suppressor in hepatocellular carcinoma by triggering the Notch signaling pathway.American journal of translational research · 2023Article
- Aberrant phosphorylation inactivates Numb in breast cancer causing expansion of the stem cell pool.The Journal of cell biology · 2022Article
- NUMB facilitates autophagy initiation through targeting SCFCell death and differentiation · 2022Article
- A review of alcohol-pathogen interactions: New insights into combined disease pathomechanisms.Alcoholism, clinical and experimental research · 2022Review
- ING4 Promotes Stemness Enrichment of Human Renal Cell Carcinoma Cells Through Inhibiting DUSP4 Expression to Activate the p38 MAPK/type I IFN-Stimulated Gene Signaling Pathway.Frontiers in pharmacology · 2022Article
- The role of NUMB/NUMB isoforms in cancer stem cells.BMB reports · 2021Review
- Drug resistance and Cancer stem cells.Cell communication and signaling : CCS · 2021Review
- N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver TumorigenesisFrontiers in oncology · 2021Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
unlabelledStem cell populations are maintained through self-renewing divisions in which one daughter cell commits to a particular fate whereas the other retains the multipotent characteristics of its parent. The NUMB, a tumor suppressor, in conjunction with another tumor-suppressor protein, p53, preserves this property and acts as a barrier against deregulated expansion of tumor-associated stem cells. In this context, NUMB-p53 interaction plays a crucial role to maintain the proper homeostasis of both stem cells, as well as differentiated cells. Because the molecular mechanism governing the assembly and stability of the NUMB-p53 interaction/complex are poorly understood, we tried to identify the molecule(s) that govern this process. Using cancer cell lines, tumor-initiating cells (TICs) of liver, the mouse model, and clinical samples, we identified that phosphorylations of NUMB destabilize p53 and promote self-renewal of TICs in a pluripotency-associated transcription factor NANOG-dependent manner. NANOG phosphorylates NUMB by atypical protein kinase C zeta (aPKCζ), through the direct induction of Aurora A kinase (AURKA) and the repression of an aPKCζ inhibitor, lethal (2) giant larvae. By radioactivity-based kinase activity assays, we showed that NANOG enhances kinase activities of both AURKA and aPKCζ, an important upstream process for NUMB phosphorylation. Phosphorylation of NUMB by aPKCζ destabilizes the NUMB-p53 interaction and p53 proteolysis and deregulates self-renewal in TICs.
conclusionPost-translational modification of NUMB by the NANOG-AURKA-aPKCζ pathway is an important event in TIC self-renewal and tumorigenesis. Hence, the NANOG-NUMB-p53 signaling axis is an important regulatory pathway for TIC events in TIC self-renewal and liver tumorigenesis, suggesting a therapeutic strategy by targeting NUMB phosphorylation. Further in-depth in vivo and clinical studies are warranted to verify this suggestion.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.