Elucidation of calcineurin signaling in the context of the cell cycle, centrosomes and cilia
Abstract/Contents
- Abstract
- Calcineurin, a highly conserved Ca2+ and calmodulin-activated phosphatase, has been most extensively studied in the context of the adaptive immune response. Due to its role in activating T-lymphocytes, calcineurin inhibitors were prescribed as immunosuppressant medications long before their mechanism of action was understood. Calcineurin inhibitors, cyclosporin A and FK506, revolutionized the field of organ transplantation in the 20th century, but frequently cause adverse effects in patients due to inhibition of calcineurin in non-immune tissues. This underscores the importance of systematically determining the substrates and functions for this ubiquitous enzyme throughout the body. Calcineurin is activated by Ca2+ and calmodulin, thus signaling takes place within distinct intracellular subdomains. Through proximity-dependent biotinylation studies, we discovered that calcineurin is immediately proximal to proteins found at the cytokinesis midbody and the centrosome. We thus hypothesized that calcineurin participates in cell cycle regulation. While we were unable to reproduce previous reports that calcineurin is essential for cytokinesis and localizes to the midbody, we determined that in fact a novel calcineurin signaling subdomain exists at centrosomes and primary cilia. Calcineurin localizes to centrosomes, but this localization does not seem to depend on, nor control the timing of, the cell cycle. Instead, calcineurin presence at the centrosome allows it to interact with binding partners and potential dephosphorylation substrates such as proteome of centriole 5 (POC5). Inhibition of calcineurin causes kidney epithelial cells to lose their ability to maintain cilia length homeostasis. The precise mechanism through which calcineurin regulates cilia length maintenance remains to be uncovered. This will help us determine whether cilia abnormalities underlie some of the adverse effects that immunosuppressed patients experience.
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 | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Tsekitsidou, Eirini |
|---|---|
| Degree supervisor | Cyert, Martha S, 1958- |
| Thesis advisor | Cyert, Martha S, 1958- |
| Thesis advisor | Lewis, Richard |
| Thesis advisor | Shen, Kang, 1972- |
| Thesis advisor | Stearns, Tim |
| Degree committee member | Lewis, Richard |
| Degree committee member | Shen, Kang, 1972- |
| Degree committee member | Stearns, Tim |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Eirini Tsekitsidou. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/vq433yb3762 |
Access conditions
- Copyright
- © 2022 by Eirini Tsekitsidou
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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