The Role of Securin in Tumorigenesis and Metastasis.
Authors: R. Hatcher, P. Zhang
Journal: Cancer Research (2009)

Abstract Genomic instability is a hallmark of human cancers. Spindle assembly checkpoint (SAC) is a critical cellular mechanism that prevents chromosome missegregation and aneuploidy by blocking premature separation of sister chromatids. The process of sister-chromatid separation occurs when separase cleaves Scc1 of the cohesin complex holding sister-chromatids together. The cell prevents this event from taking place untimely by establishing regulatory mechanisms on separase. Thus, the SAC, much like the DNA damage checkpoint, is essential for genome stability.Although a large body of evidence supports an intimate relationship between defects in the DNA damage checkpoint and tumorigenesis, such evidence is lacking for the spindle assembly checkpoint. Attempts to disable SAC by inactivating individual component, such as Mad2, or BubR1, yielded only unviable mice.Securin was the first identified inhibitor of separase in budding yeast as PDS1 (1, 2). Deletion of PDS1 caused genome instability and lethality when treated with nocodazole (2). Based on these results, it was hypothesized that deletion of the securin gene would accelerate tumorigenesis in mammals through inducing aneuploidy.However, when securin was knocked out in mice, the mutant mice were essentially normal and the cells derived from these mice show an intact SAC (3, 4). Although, securin null cells are compromised in their ability to grow in the presence of sub-lethal doses of nocodazole (4), indicating that securin does contribute to the proper functioning of the checkpoint. The over-expression of securin has been associated with metastasis in human breast cancer and therefore my securin knockout mice have not developed tumors.Apparently securin gain-of-function or loss-of-function does not have strong enough oncogenic activity to initiate tumor development, but perhaps in combination with a stronger oncogene tumors will develop faster and more aggressively. To test this, I am combining securin knockout with MMTV-ErbB2 transgenic mice, which develop adenocarcinomas in the mammary tissue by approximately 6 months old (5).Given the association of securin expression with metastasis, it is possible that securin may have a role in tumor cell metastasis. To test that possibility, I am taking advantage of the MMTV-ErbB2 mice again as these mice show lung metastasis by approximately 8 months old (5). Therefore, my hypothesis is that loss of securin facilitates tumor formation by destabilizing the genome as a result of mitotic errors, but may hinder metastasis because of its cell cycle unrelated functions.References:1. Yamamoto, A., Guacci, V., and Koshland, D. (1996a). J. Cell Biol. 133, 85–97.2. Yamamoto, A., Guacci, V., and Koshland, D. (1996b). J. Cell Biol. 133, 99–110.3. Mei, J., Huang, X., and Zhang, P. (2001). Curr. Biol. 11, 1197–1201.4. Huang, X., Hatcher, R., York, P., Zhang, P.(2005). Mol. Bio. of the Cell. 16, 4725–4732.5. Muller WJ; Sinn E; Pattengale PK; Wallace R; Leder P. 1988. Cell 54(1):105-15. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6172.