Oncogenic Serine 45-Deleted β-Catenin Remains Susceptible to Wnt Stimulation and APC Regulation in Human Colonocytes
| Autor: | Aaron J. Rudeen, Kristi L. Neufeld, Taybor W. Parker |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Adenomatous polyposis coli colorectal cancer medicine.disease_cause lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine medicine Mutation biology just-right signaling Wnt signaling pathway β-catenin lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Wnt signaling Cell biology APC 030104 developmental biology Oncology 030220 oncology & carcinogenesis Catenin biology.protein Phosphorylation Signal transduction Carcinogenesis WNT3A |
| Zdroj: | Cancers, Vol 12, Iss 2114, p 2114 (2020) Cancers Volume 12 Issue 8 |
| ISSN: | 2072-6694 |
| Popis: | The Wnt/&beta catenin signaling pathway is deregulated in nearly all colorectal cancers (CRCs), predominantly through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC mutation is thought to allow a &ldquo just-right&rdquo amount of Wnt pathway activation by fine-tuning &beta catenin levels. While at a much lower frequency, mutations that result in a &beta catenin that is compromised for degradation occur in a subset of human CRCs. Here, we investigate whether one such &ldquo stabilized&rdquo &beta catenin responds to regulatory stimuli, thus allowing &beta catenin levels conducive for tumor formation. We utilize cells harboring a single mutant allele encoding Ser45-deleted &beta catenin (&beta cat&Delta S45) to test the effects of Wnt3a treatment or APC-depletion on &beta S45 regulation and activity. We find that APC and &beta S45 retain interaction with Wnt receptors. Unexpectedly, &beta S45 accumulates and activates TOPflash reporter upon Wnt treatment or APC-depletion, but only accumulates in the nucleus upon APC loss. Finally, we find that &beta catenin phosphorylation at GSK-3&beta sites and proteasomal degradation continue to occur in the absence of Ser45. Our results expand the current understanding of Wnt/&beta catenin signaling and provide an example of a &beta catenin mutation that maintains some ability to respond to Wnt, a possible key to establishing &beta catenin activity that is &ldquo for tumorigenesis. |
| Databáze: | OpenAIRE |
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