Constitutively Active Mutant Checkpoint Kinase 1 Stops Cancer Growth

Cdc25, when phosphorylated on serine 216 by Chk1 becomes bound by an adaptor protein in the cytoplasm. It is now prevented from removing the inhibiting phosphate from MPF (mitotic/maturation promoting factor). Consequently, the cell is unable to enter mitosis.

Investigators at Case Western Reserve University (Cleveland, OH, USA) have recently published two papers defining the role of Chk1 and suggesting the possibility that genomic or drug treatment to maintain the active form of Chk1 could be a novel treatment for cancer that would supplement or replace chemotherapy and radiation treatment.

In the July 20, 2012, online edition of the Journal of Biological Chemistry the investigators reported that they had identified two highly conserved motifs (CM1 and CM2) at the C terminus of Chk1 that functioned as a nuclear export signal and nuclear localization signal, respectively. Mutating five highly conserved residues within these two motifs of Chk1 resulted in its accumulation mainly in the cytoplasm. These cytoplasmic Chk1 mutants were less stable and exhibited significantly reduced phosphorylation by DNA damage treatment. Using an adenovirus-mediated gene targeting technique the investigators showed that it was not possible to obtain homozygous mutant cancer-cell lines, and that even heterozygous mutant cell lines showed cell survival defects accompanied by spontaneous cell death.

A paper published in the August 1, 2012, online edition of the journal Cancer Research confirmed that the two point mutations rendered Chk1 constitutively active, and that expression of the constitutively active mutant form of Chk1 inhibited cancer cell proliferation.

"We have identified a new direction for cancer therapy and the new direction is leading us to a reduction in toxicity in cancer therapy, compared with chemotherapy or radiation therapy," said Dr. Youwei Zhang, assistant professor of pharmacology at Case Western Reserve University. "With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors."

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