TY - JOUR
T1 - The putative oncogene CEP72 inhibits the mitotic function of BRCA1 and induces chromosomal instability
AU - Lüddecke, S.
AU - Ertych, N.
AU - Stenzinger, A.
AU - Weichert, W.
AU - Beissbarth, T.
AU - Dyczkowski, J.
AU - Gaedcke, J.
AU - Valerius, O.
AU - Braus, G. H.
AU - Kschischo, M.
AU - Bastians, H.
N1 - Funding Information:
We thank Linda Wordeman, Sigrid Hoyer-Fender, Bert Vogelstein, Ingrid Hoffmann and Olaf Stemmann for materials and Heike Krebber for microscopy support. We thank Dennis Vollweiter and Eric Schoger for general lab support. We thank the TCGA Research Network (http://cancergenome.nih.gov/) for the open access of gene expression data. This work was supported by the Deutsche Forschungsgemeinschaft (HB and GHB) and by a DFG funded Heisenberg professorship awarded to HB.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - BRCA1 is a tumor-suppressor gene associated with, but not restricted to, breast and ovarian cancer and implicated in various biological functions. During mitosis, BRCA1 and its positive regulator Chk2 are localized at centrosomes and are required for the regulation of microtubule plus end assembly, thereby ensuring faithful mitosis and numerical chromosome stability. However, the function of BRCA1 during mitosis has not been defined mechanistically. To gain insights into the mitotic role of BRCA1 in regulating microtubule assembly, we systematically identified proteins interacting with BRCA1 during mitosis and found the centrosomal protein Cep72 as a novel BRCA1-interacting protein. CEP72 is frequently upregulated in colorectal cancer tissues and overexpression of CEP72 mirrors the consequences of BRCA1 loss during mitosis. In detail, the overexpression of CEP72 causes an increase in microtubule plus end assembly, abnormal mitotic spindle formation and the induction of chromosomal instability. Moreover, we show that high levels of Cep72 counteract Chk2 as a positive regulator of BRCA1 to ensure proper mitotic microtubule assembly. Thus, CEP72 represents a putative oncogene in colorectal cancer that might negatively regulate the mitotic function of BRCA1 to ensure chromosomal stability.
AB - BRCA1 is a tumor-suppressor gene associated with, but not restricted to, breast and ovarian cancer and implicated in various biological functions. During mitosis, BRCA1 and its positive regulator Chk2 are localized at centrosomes and are required for the regulation of microtubule plus end assembly, thereby ensuring faithful mitosis and numerical chromosome stability. However, the function of BRCA1 during mitosis has not been defined mechanistically. To gain insights into the mitotic role of BRCA1 in regulating microtubule assembly, we systematically identified proteins interacting with BRCA1 during mitosis and found the centrosomal protein Cep72 as a novel BRCA1-interacting protein. CEP72 is frequently upregulated in colorectal cancer tissues and overexpression of CEP72 mirrors the consequences of BRCA1 loss during mitosis. In detail, the overexpression of CEP72 causes an increase in microtubule plus end assembly, abnormal mitotic spindle formation and the induction of chromosomal instability. Moreover, we show that high levels of Cep72 counteract Chk2 as a positive regulator of BRCA1 to ensure proper mitotic microtubule assembly. Thus, CEP72 represents a putative oncogene in colorectal cancer that might negatively regulate the mitotic function of BRCA1 to ensure chromosomal stability.
UR - http://www.scopus.com/inward/record.url?scp=84940054780&partnerID=8YFLogxK
U2 - 10.1038/onc.2015.290
DO - 10.1038/onc.2015.290
M3 - Article
C2 - 26300001
AN - SCOPUS:84940054780
SN - 0950-9232
VL - 35
SP - 2398
EP - 2405
JO - Oncogene
JF - Oncogene
IS - 18
ER -
