The regulation of GLI1 in basal cell carcinoma
Abstract/Contents
- Abstract
- Investigations into the hedgehog (Hh) signaling cascade in increasingly complex metazoan model systems has revealed complex regulation of the GLI transcription factors to control proliferation, stemness, and ultimately oncogenic transformation. Through the study of perturbations to the hedgehog pathway in the setting of drug-resistance in Basal Cell Carcinoma (BCC), we elucidate a previously unappreciated nuclear GLI1 maturation cycle. Upstream blockade of cytoplasmic Hh activators in BCC results in the hyperactivation of the kinase aPKC and the deacetylase HDAC1 to sustain high Hh output. We find that these resistance genes act sequentially to promote the nuclear deacetylation of GLI1. Acetylated GLI1 (AcGLI1) is locked in the nucleus in a transcriptionally inactive complex on the inner nuclear membrane comprised of LAP2beta. The sequential activities of aPKC and HDAC1 rescue GLI1 off of the inner nuclear membrane, associating alternately with the nucleoplasmic co-activator LAP2alpha. The LAP2 proteins antagonize GLI1 nuclear export, ultimately facilitating transcriptional output by promoting nuclear accumulation and chromatin association. Mechanisms to disrupt all components of this GLI1 chaperoning system hold considerable promise for the treatment of advanced BCC.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Mirza, Amar |
|---|---|
| Degree supervisor | Oro, Anthony, 1958- |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Jackson, Peter K. (Peter Kent) |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Weis, William I |
| Degree committee member | Jackson, Peter K. (Peter Kent) |
| Degree committee member | Khavari, Paul A |
| Degree committee member | Weis, William I |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Amar Naeem Mirza. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/my551ch6152 |
Access conditions
- Copyright
- © 2021 by Amar Mirza
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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