ORCID ID
Graduation Date
Spring 5-4-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Jixin Dong
Abstract
Pancreatic cancer is a highly lethal disease worldwide. Given the limited effectiveness of current regimens in restricting tumor progression, it is imperative that potential molecular targets be identified to offer valuable insights into alternative therapeutics. By using a phosphate-binding tag (Phos-tag) technique, previous studies have identified several Hippo pathway-related proteins and kinases required for cancer growth or paclitaxel resistance. This work has screened various phosphatases and cyclins/cyclin-dependent kinases (CDKs) as potential cancer targets, but specifically focuses on characterizing the roles of carboxy-terminal domain small phosphatase like 2 (CTDSPL2), apoptosis-stimulating protein of p53-2 (ASPP2), and Cyclin K in pancreatic cancer.
CTDSPL2 belongs to the small CTD phosphatase family and harbors phosphatase activity toward CTD of RNA polymerase II. The role of CTDSPL2 in cancer remains unclear. Our study demonstrates that CTDSPL2 is required for pancreatic cancer cell mitosis, proliferation, and motility. Furthermore, a CDK1-mediated phosphorylation mechanism of CTDSPL2 in mitosis is revealed.
ASPP2 belongs to the ASPP family of p53 interacting proteins. It also serves as a regulatory subunit of protein phosphatase 1 (PP1). While ASPP2 is widely accepted as a tumor suppressor, ASPP2-PP1 complex activates oncogenic yes-associated protein (YAP). These contradictory findings lead us to interrogate the role of ASPP2 in cancer. We find that ASPP2 is essential for pancreatic cancer growth, and YAP is the central player for ASPP2-mediated gene expression. Additionally, the phosphorylation mechanism of ASPP2 during mitosis is investigated.
Cyclin K, the regulatory subunit of CDK12 and CDK13, regulates phosphorylation of CTD and controls the transcription of genes involved in the DNA damage response, DNA replication, and cancer signaling transduction. Nevertheless, the role of Cyclin K in pancreatic cancer is unknown. This work finds that Cyclin K depletion contributes to attenuated pancreatic cancer growth (or tumor regression) in different animal models. With current Cyclin K-degrading drugs, the druggability of Cyclin K and therapeutic potential are examined.
In conclusion, studies in this dissertation characterize the functions and regulations of CTDSPL2, ASPP2, and Cyclin K in pancreatic cancer, providing promising targets for future therapeutic interventions.
Recommended Citation
Xiao, Yi, "Identification of Mitotic Phosphatases and Cyclin K as Novel Molecular Targets in Pancreatic Cancer" (2024). Theses & Dissertations. 818.
https://digitalcommons.unmc.edu/etd/818
Comments
2024 Copyright, the authors