Overexpression of Separase induces aneuploidy and mammary tumorigenesis.

Abstract

Separase is an endopeptidase that separates sister chromatids by cleaving cohesin Rad21 during the metaphase-to-anaphase transition. Conditional expression of Separase in tetracycline-inducible diploid FSK3 mouse mammary epithelial cells with both p53 WT and mutant (Ser-233-234) alleles of unknown physiological significance develops aneuploidy within 5 days of Separase induction in vitro. Overexpression of Separase induces premature separation of chromatids, lagging chromosomes, and anaphase bridges. In an in vivo mouse mammary transplant model, induction of Separase expression in the transplanted FSK3 cells for 3-4 weeks results in the formation of aneuploid tumors in the mammary gland. Xenograft studies combined with histological and cytogenetic analysis reveal that Separase-induced tumors are clonal in their genomic complements and have a mesenchymal phenotype suggestive of an epithelial-mesenchymal transition. Induction of Separase resulted in trisomies for chromosomes 8, 15, and 17; monosomy for chromosome 10; and amplification of the distal region of chromosomes 8 and 11. Separase protein is found to be significantly overexpressed in human breast tumors compared with matched normal tissue. These results collectively suggest that Separase is an oncogene, whose overexpression alone in mammary epithelial cells is sufficient to induce aneuploidy and tumorigenesis in a p53 mutant background.

• Authors: Nenggang Zhang, Gouquing Ge, Rene Meyer, Sumita Sethi, Dipanjan Basu, Subhashree Pradhan, Yi-Jue Zhao, Xiao-Nan Li, Wei-Wen Cai, Adel K El-Naggar, Veerabhadran Baladandayuthapani, Frances S Kittrell, Pulivarthi H Rao, Daniel Medina, Debananda Pati
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 35 Pg. 13033-8 (Sep 02 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18728194 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Endopeptidases
• ESPL1 protein, human
• Separase
• Tetracycline

Topics

• Anaphase
• Aneuploidy
• Animals
• Blotting, Western
• Breast Neoplasms (enzymology)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Chromatids (enzymology)
• Chromosomal Instability
• Endopeptidases (metabolism)
• Epithelial Cells (enzymology, pathology)
• Female
• Humans
• Mammary Neoplasms, Experimental (enzymology)
• Metaphase
• Mice
• Nucleic Acid Hybridization
• Separase
• Tetracycline