| Cancer cells prevail by evading surveillance mechanisms that orchestrate cellular quiescence and cell death. Genetic alterations in key checkpoint regulators of cell cycle progression and cell death contribute to the tumor initiation, progression, and treatment resistance. Despite advances in unraveling the molecular mechanisms that underlie cell cycle commitment in cancer cells, little is known about mechanisms governing defective M-phase checkpoints. Survivin represents a mitotic gene-product overexpressed in cancer cells, intimately linked to both cell survival and cell division. Data presented here identify a novel apoptotic checkpoint at mitosis regulated by survivin phosphorylation. In normal cell division, p34cdc2-cyclin B1 phosphorylation of survivin at Thr34 promotes survivin protein stability and complex formation with caspase-9, culminating in successful transit through mitosis. Conversely, lack of survivin phosphorylation results in disassembly of a survivin-caspase-9 complex from the mitotic apparatus and mitotic cell death involving caspase-9 activation. Targeting Thr34 phosphorylation, using sequential chemotherapeutics and gene transfer techniques, has proven to be effective in facilitating cancer cell death in culture and in repressing tumor growth in a xenograft breast cancer model. Although the selective advantage provided by survivin overexpression in cancer cells remains unclear, phosphorylation of survivin clearly provides insight into survivin function at mitosis. |
