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

Nat Commun. 2017 Jan 17:8:14059. doi: 10.1038/ncomms14059.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Motifs
  • Animals
  • Cell Cycle
  • Checkpoint Kinase 2 / genetics
  • Checkpoint Kinase 2 / metabolism
  • Female
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • LIM Domain Proteins / chemistry
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Neoplasms / radiotherapy*
  • Phosphorylation
  • Protein Domains
  • Radiation Tolerance
  • Young Adult
  • cdc25 Phosphatases / chemistry
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism*

Substances

  • FHL1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • KMT2A protein, human
  • LIM Domain Proteins
  • Muscle Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Checkpoint Kinase 2
  • cdc25 Phosphatases