CK1α Plays a Central Role in Mediating MDM2 Control of p53 and E2F-1 Protein Stability
Open accessAbstract
The ubiquitin ligase murine double minute clone 2 (MDM2) mediates ubiquitination and degradation of the tumor suppressor p53. The activation and stabilization of p53 by contrast is maintained by enzymes catalyzing p53 phosphorylation and acetylation. Casein kinase 1 (CK1) is one such enzyme; it stimulates p53 after transforming growth factor-beta treatment, irradiation, or DNA virus infection. We analyzed whether CK1 regulates p53 protein stability in unstressed conditions. Depletion of CK1 using small interfering RNA or inhibition of CK1 using the kinase inhibitor (D4476) activated p53 and destabilized E2F-1, indicating that steady-state levels of these proteins are controlled by CK1. Co-immunoprecipitation of endogenous CK1 with MDM2 occurred in undamaged cells, indicating the existence of a stable multiprotein complex, and as such, we evaluated whether the MDM2 Nutlin had similar pharmacological properties to the CK1 inhibitor D4476. Indeed, D4476 or Nutlin treatments resulted in the same p53 and E2F-1 steady-state protein level changes, indicating that the MDM2 x CK1 complex is both a negative regulator of p53 and a positive regulator of E2F-1 in undamaged cells. Although the treatment of cells with D4476 resulted in a partial p53-dependent growth arrest, the induction of p53-independent apoptosis by D4476 suggested a critical role for the MDM2 x CK1 complex in maintaining E2F-1 anti-apoptotic signaling. These data highlighting a pharmacological similarity between MDM2 and CK1 small molecule inhibitors and the fact that CK1 and MDM2 form a stable complex suggest that the MDM2 x CK1 complex is a component of a genetic pathway that co-regulates the stability of the p53 and E2F-1 transcription factors.
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CK1α phosphorylates and activates MDM2, an E3 ubiquitin ligase that promotes the degradation of the P53 tumor suppressor.
“cK1α phosphorylates and activates MDM2, an e3 ubiquitin ligase that promotes the degradation of the P53 tumor suppressor (Huart et al. 2009) (Figure 5B, ii).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Huart et al. 2009
The Discussion (page not provided) says CK1α associates with MDM2 and may maintain it in a form favoring MDM2 activity; the paper also says MDM2 mediates p53 ubiquitination and degradation. It does not establish as fact that CK1α phosphorylates and activates MDM2: the Discussion frames phosphorylation as a hypothesis, and the Additional information section says whether the interaction depends on phosphorylation or kinase docking remains undetermined. (LLM, conf=0.88)
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- Authors
- Huart, A.-S., MacLaine, N. J., Meek, D. W., & Hupp, T. R.
- Affiliations
- Edinburgh Cancer Research (GB)
- University of Dundee (GB)
- Corresponding author
- Hupp, Ted R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 284
- Issue
- 47
- Pages
- 32384-32394
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2781653
- OpenAlex
- W2112479239
- Cited by
- 110
- References
- 26
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 21 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 11 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 8 · 2014: 5 · 2013: 7 · 2012: 9
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Cancer Research UK (C483/A10706)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- casein kinase 1, CK1α, MDM2, p53, E2F1, protein stability, ubiquitination, p53 phosphorylation, p53 acetylation, nutlin, anti-apoptotic signaling, p53-independent apoptosis, tumor suppressor regulation
- MeSH terms
- Benzamides, Cell Cycle, Humans, Imidazoles, Models, Biological, Phosphorylation, Piperazines, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Protein Isoforms, RNA, Small Interfering, Cell Line, Tumor, Casein Kinase I, E2F1 Transcription Factor, Proto-Oncogene Proteins c-mdm2
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