TY - JOUR
T1 - Calcineurin regulates cyclin D1 stability through dephosphorylation at T286
AU - Goshima, Takahiro
AU - Habara, Makoto
AU - Maeda, Keisuke
AU - Hanaki, Shunsuke
AU - Kato, Yoichi
AU - Shimada, Midori
N1 - Funding Information:
We thank for Drs T. Toyama and Y. Johmura for critical discussions, Ms. N. Kawasaki, Dr. C. Yamada, Ms. M. Ohama and Mr. Y. Sato for technical assistance. This work was supported by the Research Fellowships of Japanese Society for the Promotion of Science (Grant Number 18H02681) (M.S.), and a grant from MSD Life Science Foundation, Public Interest Incorporated Foundation (M.S.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The Calcineurin/NFAT (nuclear factor of activated T cells) pathway plays an essential role in the tumorigenic and metastatic properties in breast cancer. The molecular mechanism of the antiproliferative effect of calcineurin inhibition, however, is poorly understood. We found that calcineurin inhibition delayed cell cycle progression at G1/S, and promoted cyclin D1 degradation by inhibiting dephosphorylation at T286. Importantly, overexpression of cyclin D1 partially rescued delayed G1/S progression, thereby revealing cyclin D1 as a key factor downstream of calcineurin inhibition. Cyclin D1 upregulation is observed in human invasive breast cancers, and our findings indicate that dysregulation of T286 phosphorylation could play a role in this phenomenon. We therefore propose that targeting site specific phosphorylation of cyclin D1 could be a potential strategy for clinical intervention of invasive breast cancer.
AB - The Calcineurin/NFAT (nuclear factor of activated T cells) pathway plays an essential role in the tumorigenic and metastatic properties in breast cancer. The molecular mechanism of the antiproliferative effect of calcineurin inhibition, however, is poorly understood. We found that calcineurin inhibition delayed cell cycle progression at G1/S, and promoted cyclin D1 degradation by inhibiting dephosphorylation at T286. Importantly, overexpression of cyclin D1 partially rescued delayed G1/S progression, thereby revealing cyclin D1 as a key factor downstream of calcineurin inhibition. Cyclin D1 upregulation is observed in human invasive breast cancers, and our findings indicate that dysregulation of T286 phosphorylation could play a role in this phenomenon. We therefore propose that targeting site specific phosphorylation of cyclin D1 could be a potential strategy for clinical intervention of invasive breast cancer.
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U2 - 10.1038/s41598-019-48976-7
DO - 10.1038/s41598-019-48976-7
M3 - Article
C2 - 31484966
AN - SCOPUS:85071748659
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 12779
ER -