Abstract 4138: Investigating the relationship between DUSP12 and ZPR9 in cell division and death

Abstract Protein phosphatases regulate essential processes in human cells and have critical roles in many human diseases, including cancer. The dual-specific phosphatases (DUSPs) are a subset of protein phosphatases that have become increasingly implicated in human cancers over the past decade. DUSP12 is a poorly characterized atypical DUSP widely conserved throughout evolution. While DUSP12 has been shown to possess pro-survival attributes, it is unclear if this is related to its potential role in cell division. Specifically, DUSP12 has been shown to play a role in both cell death and proliferation, acting in a protective capacity against stressful conditions in both hepatic and myocardial ischemic-reperfusion injury. Interestingly, several studies have also linked aberrant expression of DUSP12 to the development of a wide range of cancers, highlighting the importance of investigating the biological activities of DUSP12 as it appears that dissecting its functions in detail can provide insight into new mechanisms supporting uncontrolled cell growth. More recent evidence further suggests that DUSP12 affects cell cycle progression by regulating DNA content at the G1/S and G2/M checkpoints, likely through its unique zinc binding domain. However, the lack of known DUSP12 targets has hindered our understanding of the biological significance of this unique enzyme. From preliminary proteomic analyses of DUSP12 using affinity- and proximity-based approaches coupled to mass spectrometry, we identified ZPR9 as a potential interactor of DUSP12 which has been validated by in-cell and in-vitro immunoprecipitation assays. Previous studies have shown that ZPR9 may play a role in apoptosis, but it is unclear if and how ZPR9 participates in cell division and, more so, how it promotes cell death. Using cancer cell lines as a model system and leveraging advanced imaging techniques, I am performing follow-up functional studies to determine if and how ZPR9 is modified by DUSP12 and, further, if modification of ZPR9 by DUSP12 is important in influencing improper cell division. Collectively, this work will provide insights into the mechanism and regulatory role of the phosphatase DUSP12 during cell division as well as form the basis for designing novel therapeutic approaches to address diseases associated with abnormal proliferation. Citation Format: Mai Abdusamad, Xiao Guo, Ivan Ramirez, Whitaker Cohn, Erick Velasquez, Ankur Gholkar, Julian P. Whitelegge, Jorge Z. Torres. Investigating the relationship between DUSP12 and ZPR9 in cell division and death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4138.