Abstract 2974: Cep57 is a novel regulator of centriole overduplication in tumor cells

Abstract

Abstract Abnormal multipolar mitoses are commonly observed in human cancers where they can increase the risk for chromosome segregation errors, numerical chromosomal instability and malignant progression. The mitotic spindle poles are formed by centrosomes and tumor cells frequently show abnormal centrosomes numbers. The molecular mechanisms leading to numerical centrosome aberrations are not understood in detail. The centrosome consists of two centrioles, which normally duplicate in synchrony with the cell division cycle. We recently identified a novel mechanisms leading to abnormal centriole numbers in tumor cells in which maternal centrioles generate more than the normal one daughter at the same time (centriole multiplication). Using a siRNA library screen enriched for centrosomal proteins, we identified Cep57 as a novel protein involved in centriole multiplication. Cep57 was found to localize to centrosomes and to co-localize and functionally interact with Polo-like kinase 4 (PLK4), a master regulator of centriole duplication control. Cep57 overexpression was found to promote abnormal centrosome and centriole numbers as well as mitotic abnormalities with a significant number of cells showing multipolar metaphases as well as multipolar anaphases and telophases. Cep57 maps to chromosome 11q21, a region that is amplified in several cancer types including hematological malignancies and prostate cancer. Taken together, we identified Cep57 as regulator of centriole duplication in tumor cells and a candidate oncogene. Experiments to target the Cep57-PLK4 axis with small molecules to prevent cell division errors and malignant progression are currently under way. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2974.