Down regulation of Chk1 by p53 plays a role in synergistic induction of apoptosis by chemotherapeutics and inhibitors for Jak2 or BCR/ABL in hematopoietic cells
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Yoshihiro Umezawa1, Tetsuya Kurosu1, Hiroki Akiyama1, Nang Wu1, Ayako Nogami1, Toshikage Nagao1, Osamu Miura1
1Department of Hematology, Graduate School of Medical and Dental Sciences, and Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
Osamu Miura, email: firstname.lastname@example.org
Keywords: Chk1, p53, BCR/ABL, Jak2, chemotherapeutics
Received: February 17, 2016 Accepted: May 20, 2016 Published: June 06, 2016
DNA-damaging chemotherapeutic agents activate apoptotic pathways in cancer cells. However, they also activate checkpoint mechanisms mainly involving Chk1 and p53 to arrest cell cycle progression, thus abbreviating their cytotoxic effects. We previously found that aberrant tyrosine kinases involved in leukemogenesis, such as BCR/ABL and Jak2-V617F, as well as Jak2 activated by hematopoietic cytokines enhance Chk1-mediated G2/M arrest through the PI3K/Akt/GSK3 pathway to confer resistance to chemotherapeutic agents, which was prevented by inhibition of these kinases or the downstream PI3K/Akt pathway. However, the possible involvement of p53 in regulation of Chk1-mediated G2/M checkpoint has remained to be elucidated. We demonstrate here that a dominant negative mutant of p53, p53-DD, increases Chk1-mediated G2/M checkpoint activation induced by chemotherapeutics and protects it from down regulation by inhibition of Jak2, BCR/ABL, or the PI3K/Akt pathway in hematopoietic model cell lines 32D and BaF3 or their transformants by BCR/ABL. Consistent with this, the p53 activator nutlin-3 synergistically induced apoptosis with chemotherapeutics by inhibiting Chk1-mediated G2/M arrest in these cells, including cells transformed by the T315I mutant of BCR/ABL resistant to various kinase inhibitors in clinical use. Further studies suggest that p53 may inhibit the Chk1 pathway by its transcription-dependent function and through mechanisms involving the proteasomal system, but not the PI3K/Akt/GSK3 pathway. The present study may shed a new light on molecular mechanisms for the therapy resistance of p53-mutated hematological malignancies and would provide valuable information for the development of novel therapeutic strategies against these diseases with dismal prognosis.
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