By studying the effects of radiation and other stresses on the pathway that normally regulate Chk1, the researchers discovered that the same pathway that activates Chk1 via phosphorylation by its regulatory enzyme, ATR, also marks Chk1 for eventual destruction.
"We expect this process prevents activated Chk1 from accumulating in normal cells and prevents abnormal cell proliferation," said Abraham. "ATR activates, but also destabilizes Chk1, which creates a homeostatic mechanism that balances the genome protective function of Chk1 with the process of cell proliferation. This is a new look at drug therapy. Textbook descriptions of ATR and Chk1 don't describe this dual role."
"The findings also provide further insight into Chk1 activation and tumor sensitivity," Abraham added. "Cancer cells rely heavily on Chk1 for survival and proliferation under stressful environmental conditions. Instead of halting abnormal growth of cancer cells, drug therapy could in effect induce Chk1 natural activity to prevent cell death in cancer cells."
Collaborators on this publication include You-wei Zhang, Diane M. Otterness, and Gary Chiang from Dr. Abraham's laboratory at The Burnham Institute; and Weilin Xie, and Franklin Mercurio of Celgene Corporation; and Yun-Cai Liu of La Jolla Institute for Allergy and Immunology.