title: A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity.
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.
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning 116023, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.|Department of Oncology, PLA General Hospital, Beijing 100853, China.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.|Department of Thoracic Surgery, Hainan Branch of PLA General Hospital, Hainan 572013, China.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Medical Research Center of Shengjing Hospital, China Medical University, Liaoning 110004, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Gynecology and Obstetrics, PLA General Hospital, Beijing 100853, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Endocrinology, PLA General Hospital, Beijing 100853, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, PLA General Hospital, Beijing 100853, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Thoracic Surgery, PLA General Hospital, Beijing 100853, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery, PLA General Hospital, Beijing 100853, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Oncology, 307 Hospital of People's Liberation Army, Beijing 100071, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Hong
authors.affiliation: Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing 100142, China.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710061, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710061, China.
authors.forename: Shenbo
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Oncology, PLA General Hospital, Beijing 100853, China.
authors.forename: Shunchang
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning 116023, China.
authors.forename: Qinong
authors.initials: Q
authors.lastname: Ye
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020816:Amino Acid Motifs; D000818:Animals; D002453:Cell Cycle; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000532:radiotherapy*; D010766:Phosphorylation; D000072417:Protein Domains; D011836:Radiation Tolerance; D055815:Young Adult; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D064447:Checkpoint Kinase 2; D020687:cdc25 Phosphatases