Abstract
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.
Highlights
Chemotherapeutic agents generally induce DNA damages to activate apoptotic pathways in cancer cells [1]
We demonstrate that a dominant negative mutant of p53, p53-DD, enhances Chk1-mediated G2/M checkpoint activation induced by chemotherapeutics and prevents its down regulation by inhibitors for Jak2, BCR/ABL, or the PI3K/Akt pathway in hematopoietic model cell lines 32D and BaF3 or their transformants by BCR/ABL
A dominant negative mutant of p53, p53-DD, enhances Chk1-mediated G2/M checkpoint activation induced by chemotherapeutics in hematopoietic cells
Summary
Chemotherapeutic agents generally induce DNA damages to activate apoptotic pathways in cancer cells [1]. The G2/M arrest is mainly mediated by activation of the serine/threonine kinase Chk, which is activated by phosphorylation on S317 and S345 by the DNA damage-activated ATR kinase in response to genotoxic stress and inhibits the Cdc phosphatases, increasing the level of inhibitory phosphorylation of Cdc on Tyr and Thr to arrest the G2/M transition [2]. In the absence of stress, p53 is tightly controlled by Mdm, which associates with p53 to induce its ubiquitination and degradation. In response to cellular stress, including DNA damages, the p53 level is elevated by post-translational mechanisms that interfere with its interaction with Mdm. Activated ATR and Chk induce p53 expression by phosphorylating S15 and S20 on p53 to prevent its association with Mdm2 [4, 5]. The possible involvement of p53 in regulation of Chk1-mediated G2/M checkpoint has remained to be elucidated
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