c-MYB is a transcriptional regulator of ESPL1/Separase in BCR-ABL-positive chronic myeloid leukemia

被引：8
作者：
Prinzhorn W. [1 ]
Stehle M. [1 ]
Kleiner H. [1 ]
Ruppenthal S. [1 ]
Müller M.C. [1 ]
Hofmann W.-K. [1 ]
Fabarius A. [1 ]
Seifarth W. [1 ]
机构：
[1] Medizinische Klinik (Hämatologie und Onkologie), Wissenschaftliches Labor, Medizinische Fakultät Mannheim der Universität Heidelberg, Pettenkofer Str. 22, Mannheim
来源：
Biomarker Research | / 4卷 / 1期
关键词：
BCR-ABL; C-MYB; CML; ESPL1/Separase; Genomic stability; Imatinib;
D O I：
10.1186/s40364-016-0059-2
中图分类号：
学科分类号：
摘要：
Background: Genomic instability and clonal evolution are hallmarks of progressing chronic myeloid leukemia (CML). Recently, we have shown that clonal evolution and blast crisis correlate with altered expression and activity of Separase, a cysteine endopeptidase that is a mitotic key player in chromosomal segregation and centriole duplication. Hyperactivation of Separase in human hematopoietic cells has been linked to a feedback mechanism that posttranslationally stimulates Separase proteolytic activity after imatinib therapy-induced reduction of Separase protein levels. Methods and Results: In search for potential therapy-responsive transcriptional mechanisms we have investigated the role of the transcription factor c-MYB for Separase expression in CML cell lines (LAMA-84, K562, BV-173) and in clinical samples. Quantitative RT-PCR and Western blot immunostaining experiments revealed that c-MYB expression levels are decreased in an imatinib-dependent manner and positively correlate with Separase expression levels in cell lines and in clinical CML samples. RNA silencing of c-MYB expression in CML cell lines resulted in reduced Separase protein levels. Gelshift and ChIP assays confirmed that c-MYB binds to a putative c-MYB binding sequence located within the ESPL1 promoter. Conclusions: Our data suggest that ESPL1/Separase is a regulatory target of c-MYB. Therefore, c-MYB, known to be required for BCR-ABL-dependent transformation of hematopoietic progenitors and leukemogenesis, may also control the Separase-dependent fidelity of mitotic chromosomal segregation and centriole duplication essential for maintenance of genomic stability. © 2016 Prinzhorn et al.
引用
收藏
相关论文
共 65 条
[1]  
Chestukhin A., Pfeffer C., Milligan S., DeCaprio J.A., Pellman D., Processing, localization, and requirement of human separase for normal anaphase progression, Proc Natl Acad Sci U S A, 100, 8, pp. 4574-4579, (2003)
[2]  
Schockel L., Mockel M., Mayer B., Boos D., Stemmann O., Cleavage of cohesin rings coordinates the separation of centrioles and chromatids, Nat Cell Biol, 13, 8, pp. 966-972, (2011)
[3]  
Simmons-Kovacs L.A., Haase S.B., Cohesin: it's not just for chromosomes anymore, Cell Cycle, 9, 9, pp. 1750-1753, (2010)
[4]  
Uhlmann F., Secured cutting: controlling separase at the metaphase to anaphase transition, EMBO Rep, 2, 6, pp. 487-492, (2001)
[5]  
Nigg E.A., Centrosome duplication: of rules and licenses, Trends Cell Biol, 17, 5, pp. 215-221, (2007)
[6]  
Zhang N., Ge G., Meyer R., Sethi S., Basu D., Pradhan S., Et al., Overexpression of Separase induces aneuploidy and mammary tumorigenesis, Proc Natl Acad Sci U S A, 105, 35, pp. 13033-13038, (2008)
[7]  
Nigg E.A., Raff J.W., Centrioles, centrosomes, and cilia in health and disease, Cell, 139, 4, pp. 663-678, (2009)
[8]  
Chan J.Y., A clinical overview of centrosome amplification in human cancers, Int J Biol Sci, 7, 8, pp. 1122-1144, (2011)
[9]  
Meyer R., Fofanov V., Panigrahi A., Merchant F., Zhang N., Pati D., Overexpression and mislocalization of the chromosomal segregation protein separase in multiple human cancers, Clin Cancer Res, 15, 8, pp. 2703-2710, (2009)
[10]  
Mitelman F., Levan G., Nilsson P.G., Brandt L., Non-random karyotypic evolution in chronic myeloid leukemia, Int J Cancer, 18, 1, pp. 24-30, (1976)
1234567