Abstract 561: Loss of lamin A/C and p53 in mouse embroyic fibroblasts affect the cell cycle and chromosomal stability .
Authors: Rosario Santas , Capo-Chichi Deylosse C. , Moore Robert , Xu Xiang-xi M. 
Published: August 2014

Abstract
Ovarian cancer is the most lethal of gynecological cancers being the fifth leading cause of cancer-associated deaths. Reduced expression or loss of lamin A/C has been demonstrated in 47% of ovarian cancers, as well. Lamins A and C are intermediate filament proteins and are major components of the nuclear lamina that provide structure to the nucleus. Mutations in lamins A/ C are the source of several nuclear envelope diseases, namely laminopathies, such as muscular dystrophy. Interestingly, data acquired from research on laminopathy patient samples, as well as from in vitro, and in vivo murine models have revealed that tissue affected by lamin A/C mutations display characteristics similar to neoplastic or malignant cells, such as defective nuclear architecture and changes in ploidy. Further, reduced expression or loss of lamin A/C has been demonstrated in ovarian, breast, and small-cell lung cancers, and has been associated with poor outcome in gastric carcinomas and hematologic malignancies. We previously found that siRNA suppression of lamin A/C in human ovarian surface epithelial cells results in deformed nuclear morphology, p21 induction, decreased mitosis, delayed cell growth, and aneuploidy. Accordingly, we currently investigated how concomitant loss of lamin A/C and p53 (LAC/p53 KO) affect the cell cycle and chromosome content in germ line LAC/p53 knockout mouse embryonic fibroblasts (MEFs) through western blotting and flow cytometry. We found that that in nonsynchronized early and late passage LAC/p53 KO MEFs cell cycle inhibitors p16 and p19, as well as pRB, cyclin D1, and PCNA expression is upregulated compared to the lamin A/C knockout and wild type controls. Surprisingly, this expression pattern is also observed under serum-starved conditions. Cyclin D1, PCNA, and pRB expression is also substantially upregulated in late passage MEFs. Further, early and late passage LAC/p53 KO MEFs possess a considerably larger mitotic and aneuploid cell population than the controls. As lamin A/C is a fundamental structural nuclear protein, it is hypothesized that lamin A/C knockout MEFs display reduced mitosis and hindered cell growth to prevent malignancy. Additional loss of a functional cell cycle, and checkpoint protein like p53, may reverse the initial phenotype to promote tumorigenesis, particularly if chromosomal instability is already established. Our experimental results support the ideas that loss of lamin A/C protein is synergistic with p53 inactivation in promoting cell cycle progression and chromosomal instability to potentially induce tumorigenesis. The mechanism of the aforementioned findings and the potential to induce ovarian tumorigenesis are under further investigation in vivo.
Citation Format: Santas Rosario, Deylosse C. Capo-Chichi, Robert Moore, Xiang-xi M. Xu. Loss of lamin A/C and p53 in mouse embroyic fibroblasts affect the cell cycle and chromosomal stability . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 561. doi:10.1158/1538-7445.AM2013-561