Nuclear aPKC-Mediated Mechanisms of Drug Resistance in Basal Cell Carcinoma
Abstract/Contents
- Abstract
- Transcription factor trafficking requires a highly regulated process involving numerous structural proteins in the nucleus. Disruptions to these processes have been implicated in a number of diseases including the development of drug resistance in basal cell carcinoma (BCC). BCC, one of the most common forms of skin cancer, is driven by high levels of Hedgehog (Hh) signaling, a critical pathway in development that has been associated with several cancers. Previous studies have identified atypical protein kinase C (aPKC) as a key regulator of drug resistance in BCCs, which functions to maintain a high Hedgehog pathway signal in order to promote tumor growth and therefore evasion of treatment. However, while aPKC appears to alter nuclear structure, the specific mechanism through which it regulates the Hh pathway and its transcriptional output remains unclear. One hypothesis proposes that aPKC interacts with the nuclear lamina, and through this interaction can release transcription factors from the nuclear envelope. Lamins are classically involved in nuclear structural maintenance and recent findings have also elucidated their important role in transcriptional regulation, especially upon post-translational modifications. In order to analyze how aPKC interacts with the nuclear lamina, we conducted biochemical and phosphoproteomic analyses of a murine BCC cell line (ASZ0001) upon small-molecule inhibition of aPKC. Specifically, we analyzed aPKC’s phosphorylation residues in lamina via mass spectrometry of fractionated cell nuclei and evaluated the ability of nuclear lamina co-regulatory protein, LAP2α, to disrupt higher order phospho-lamin structure formation by co-immunoprecipitation-based lamin oligomerization assay. Notably, we found that interactions between aPKC and the nuclear lamina regulate the Hh pathway in BCC. In the nucleus, aPKC phosphorylates lamin A at residues near its IgG fold, including S390 and S392. Additionally, phosphorylation at these residues promotes association of lamin with LAP2α and the GLI1 transcription factor, which drives Hh signaling. These findings will aid in the discovery of future targeted therapeutics for BCC and further our understanding of transcription factor regulatory mechanisms, specifically the importance of movement between different nuclear compartments.
Description
| Type of resource | text |
|---|---|
| Date created | June 2021 |
Creators/Contributors
| Author | Ha, Sierra Kaitlyn |
|---|---|
| Primary advisor | Oro, Anthony |
| Advisor | Stearns, Tim |
| Degree granting institution | Stanford University, Department of Biology, 2021 |
Subjects
| Subject | Hedgehog |
|---|---|
| Subject | transcription factor |
| Subject | basal cell carcinoma |
| Subject | lamin |
| Subject | atypical protein kinase c |
| Subject | biology |
| Genre | Thesis |
Bibliographic information
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- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
Preferred citation
- Preferred Citation
- Ha, Sierra Kaitlyn; Oro, Anthony; Stearns, Tim. (2021). Nuclear aPKC-Mediated Mechanisms of Drug Resistance in Basal Cell Carcinoma. Stanford Digital Repository. Available at: https://purl.stanford.edu/dx012pb0637
Collection
Undergraduate Theses, Department of Biology, 2020-2021
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- sierraha@stanford.edu
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