EWS-Fli1 up-regulates expression of the Aurora A and Aurora B kinases.

Abstract

EWS-Fli1, a fusion gene resulting from the chromosomal translocation t(11;22, q24;q12), encodes a transcriptional activator, promotes cellular transformation, and is often found in Ewing sarcoma and primitive neuroectodermal tumor. The Aurora A and Aurora B kinases belong to a highly conserved family of serine/threonine protein kinases, are tightly regulated during the cell cycle, and are overexpressed in many carcinomas. Because the relationship between the Aurora A and/or Aurora B genes and the EWS-Fli1 fusion gene is unknown, we investigated the regulatory mechanism(s) by which Aurora kinases are controlled. Knockdown of EWS-Fli1 by small interfering RNA reduced mRNA levels not only of EWS-Fli1 but also of Aurora A and Aurora B. Luciferase assay using Aurora A and Aurora B promoters showed up-regulated activities compared with those of an empty vector. Experiments with deletion and point mutants showed positive regulatory Ets-binding sites located -84 and -71 bp upstream of the transcription initiation sites in Aurora A and Aurora B, respectively. Moreover, chromatin immunoprecipitation assay revealed that EWS-Fli1 gene products interact with both the Aurora A and Aurora B promoters. These results strongly suggest that the mitotic kinases Aurora A and Aurora B are regulated by EWS-Fli1 fusion protein in Ewing sarcoma cells.

• Authors: Kazuhiko Wakahara, Takatoshi Ohno, Masashi Kimura, Takahiro Masuda, Satoshi Nozawa, Taikoh Dohjima, Takatoshi Yamamoto, Akihito Nagano, Gou Kawai, Aya Matsuhashi, Mitsuru Saitoh, Iori Takigami, Yukio Okano, Katsuji Shimizu
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 6 Issue 12 Pg. 1937-45 (Dec 2008) ISSN: 1541-7786 [Print] United States
• PMID: 19074838 (Publication Type: Journal Article)

Chemical References

• EWS-FLI fusion protein
• Oncogene Proteins, Fusion
• Proto-Oncogene Protein c-fli-1
• RNA, Messenger
• RNA-Binding Protein EWS
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Aurora Kinase B
• Aurora Kinases
• Bone Neoplasms (genetics, pathology, physiopathology)
• Cell Line, Tumor
• Consensus Sequence
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Oncogene Proteins, Fusion (genetics, metabolism)
• Promoter Regions, Genetic (physiology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Protein c-fli-1 (genetics, metabolism)
• RNA, Messenger (metabolism)
• RNA-Binding Protein EWS
• Sarcoma, Ewing (genetics, pathology, physiopathology)
• Transcription, Genetic (physiology)