TY - JOUR
T1 - Nuclear export of BRCA1 occurs during early S phase and is calcium-dependent
AU - Glover-Collins, Katherine
AU - Thompson, Marilyn E.
N1 - Funding Information:
We thank Dr. E. Motley and G. Chaudhuri for reagents, Dr. S. Eltom for HMEC cells, and Drs. T. Dermody and L. Limbird for helpful comments. Experiments/data analyses were performed in part through the use of the VUMC Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404 and the John F. Kennedy Center), the Flow Cytometry Special Resource Center (Veterans' Administration Medical Center, Nashville, TN) and the DNA Core Facility (Meharry Medical College). We gratefully acknowledge the following support from the National Institutes of Health: NIH-NCRR supported Research Centers in Minority Institutions (RCMI) Grant 2G12RR03032, National Cancer Institute K01 CA89494 and U54 CA91408 (MET), National Institute of General Medical Studies T32 GM07347 (K.G-C.).
PY - 2008/5
Y1 - 2008/5
N2 - Although the breast cancer susceptibility gene 1 (BRCA1) protein is predominantly nuclear, its localization can vary during the cell cycle in response to cellular insults. For example, in S-phase cells, BRCA1 forms subnuclear foci and localizes to the perinuclear region in response to DNA damage. The present study provides evidence that BRCA1 is transiently excluded from the nucleus during the early part of S phase in the absence of DNA damage. The percentage of MCF-7 human breast cancer cells predominantly expressing nonnuclear BRCA1 significantly correlates with the percentage of cells within early S phase. This redistribution of BRCA1 is partially sensitive to leptomycin B, indicating that CRM-1-mediated nuclear export is involved. Similar results were observed with MCF-12A nonmalignant human mammary cells. The abilities of BAPTA-AM, an intracellular calcium chelator, to inhibit the change in BRCA1 localization, and of A23187, a calcium ionophore, and of thapsigargin to mimic nuclear exclusion of BRCA1, provide evidence for the involvement of calcium in this process. The calcium-mediated change in BRCA1 localization occurs in several cell lines, indicating that this effect is not cell line specific. BRCA2 localization is not affected by A23187. Furthermore, inhibition of calcium-calmodulin interaction and calcium-calmodulin dependent protein kinase II attenuates the calcium-mediated change in BRCA1 localization. These data suggest that BRCA1 nuclear export can be cell cycle-regulated by a calcium-dependent mechanism.
AB - Although the breast cancer susceptibility gene 1 (BRCA1) protein is predominantly nuclear, its localization can vary during the cell cycle in response to cellular insults. For example, in S-phase cells, BRCA1 forms subnuclear foci and localizes to the perinuclear region in response to DNA damage. The present study provides evidence that BRCA1 is transiently excluded from the nucleus during the early part of S phase in the absence of DNA damage. The percentage of MCF-7 human breast cancer cells predominantly expressing nonnuclear BRCA1 significantly correlates with the percentage of cells within early S phase. This redistribution of BRCA1 is partially sensitive to leptomycin B, indicating that CRM-1-mediated nuclear export is involved. Similar results were observed with MCF-12A nonmalignant human mammary cells. The abilities of BAPTA-AM, an intracellular calcium chelator, to inhibit the change in BRCA1 localization, and of A23187, a calcium ionophore, and of thapsigargin to mimic nuclear exclusion of BRCA1, provide evidence for the involvement of calcium in this process. The calcium-mediated change in BRCA1 localization occurs in several cell lines, indicating that this effect is not cell line specific. BRCA2 localization is not affected by A23187. Furthermore, inhibition of calcium-calmodulin interaction and calcium-calmodulin dependent protein kinase II attenuates the calcium-mediated change in BRCA1 localization. These data suggest that BRCA1 nuclear export can be cell cycle-regulated by a calcium-dependent mechanism.
KW - A23187
KW - BAPTA-AM
KW - BRCA1
KW - Calcium
KW - Cell cycle
KW - Leptomycin B
KW - Nuclear export
UR - http://www.scopus.com/inward/record.url?scp=40049091816&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2008.01.007
DO - 10.1016/j.cellsig.2008.01.007
M3 - Article
C2 - 18296025
AN - SCOPUS:40049091816
SN - 0898-6568
VL - 20
SP - 958
EP - 968
JO - Cellular Signalling
JF - Cellular Signalling
IS - 5
ER -