Abstract 3774: Investigating the role of CDC25B in inhibition of cellular proliferation

Abstract

Abstract CDC25B is a dual specificity phosphatase that activates cyclin-dependent kinases to trigger entry into mitosis and is required for re-entry into mitosis after DNA damage. Four isoforms of CDC25B are known to be expressed and some differences in their role in dividing cells versus continuation of the cell cycle after DNA damage have been shown. As an oncogene, CDC25B is upregulated by c-Myc and activated by Aurora-A. In humans, CDC25B is overexpressed in multiple tumor types and increased levels correlate with worsening tumor grade. In a transgenic mouse model, overexpression of CDC25B in the mammary glands led to accelerated mammary epithelial proliferation resulting in hyperplasia and the formation of tumors when exposed to the carcinogen DMBA. In vitro, co-transfection of CDC25B with Ras allows for transformation of MEF’s. Surprisingly, given the establishment of CDC25B as an oncogene, colony formation assays using ectopic expression of CDC25B in transformed cell lines reveal an anti-proliferative effect. Although CDC25B has been shown to cause DNA damage and activates p53, our data show that colony formation is decreased independent of p53 status. Preliminary data reveal a role for Ras inhibition as a cause of this anti-proliferative effect. Co-transfection of CDC25B and activated Ras results in decreased expression of the ectopic Ras protein in several cell lines tested. Furthermore overexpression of CDC25B abrogates the G2 arrest and decreases cell viability after pulse treatment with doxorubicin. Taken together, these data suggest a novel mechanism by which CDC25B may inhibit proliferation by decreasing Ras expression. Citation Format: Caleb C. Lee, James Manfredi. Investigating the role of CDC25B in inhibition of cellular proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3774. doi:10.1158/1538-7445.AM2015-3774