BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction

Promyelocytic leukemia protein (PML) modulates the p53 tumor suppressor through its interaction with p53 and MDM2. We found that activated BMK1 preferentially associates with PML isoform IV and disrupts PML-MDM2 interaction. Doxorubicin, a common chemotherapeutic agent, is known to promote PML-mediated p53 activation in part by promoting PML-dependent MDM2 nucleolar sequestration. We discovered that BMK1 deactivation coupled with doxorubicin synergistically enhanced MDM2 nucleolar sequestration and, consequently, promoted PML-mediated p53 up-regulation leading to tumor cell apoptosis in vitro and tumor regression in vivo. Collectively, these results not only suggest that BMK1 activity plays a role in suppressing p53 by blocking the interaction between PML and MDM2 but also implicate that pharmacological BMK1 inhibitor should significantly enhance the anti-cancer capacity of doxorubicin-based chemotherapy.