A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity

Xiaojie Xu, Zhongyi Fan, Chaoyang Liang, Ling Li, Lili Wang, Yingchun Liang, Jun Wu, Shaohong Chang, Zhifeng Yan, Zhaohui Lv, Jing Fu, Yang Liu, Shuai Jin, Tao Wang, Tian Hong, Yishan Dong, Lihua Ding, Long Cheng, Rui Liu, Shenbo Fu, Shunchang Jiao and Qinong Ye ()
Additional contact information
Xiaojie Xu: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Zhongyi Fan: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Chaoyang Liang: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Ling Li: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Lili Wang: Medical Research Center of Shengjing Hospital, China Medical University
Yingchun Liang: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Jun Wu: Beijing Institute of Biotechnology
Shaohong Chang: Beijing Institute of Biotechnology
Zhifeng Yan: PLA General Hospital
Zhaohui Lv: PLA General Hospital
Jing Fu: PLA General Hospital
Yang Liu: PLA General Hospital
Shuai Jin: PLA General Hospital
Tao Wang: 307 Hospital of People’s Liberation Army
Tian Hong: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Yishan Dong: Peking University Cancer Hospital & Institute
Lihua Ding: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Long Cheng: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine
Rui Liu: The First Affiliated Hospital of Xi’an Jiao Tong University
Shenbo Fu: The First Affiliated Hospital of Xi’an Jiao Tong University
Shunchang Jiao: PLA General Hospital
Qinong Ye: Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Tumour radiotherapy resistance involves the cell cycle pathway. CDC25 phosphatases are key cell cycle regulators. However, how CDC25 activity is precisely controlled remains largely unknown. Here, we show that LIM domain-containing proteins, such as FHL1, increase inhibitory CDC25 phosphorylation by forming a complex with CHK2 and CDC25, and sequester CDC25 in the cytoplasm by forming another complex with 14-3-3 and CDC25, resulting in increased radioresistance in cancer cells. FHL1 expression, induced by ionizing irradiation in a SP1- and MLL1-dependent manner, positively correlates with radioresistance in cancer patients. We identify a cell-penetrating 11 amino-acid motif within LIM domains (eLIM) that is sufficient for binding CHK2 and CDC25, reducing the CHK2–CDC25 and CDC25–14-3-3 interaction and enhancing CDC25 activity and cancer radiosensitivity accompanied by mitotic catastrophe and apoptosis. Our results provide novel insight into molecular mechanisms underlying CDC25 activity regulation. LIM protein inhibition or use of eLIM may be new strategies for improving tumour radiosensitivity.

Date: 2017
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DOI: 10.1038/ncomms14059

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