Abstract
Previously, heat shock factor 1 (HSF1) had been reported to induce genomic instability and aneuploidy by interaction with Cdc20. Here, we have further examined the functions of HSF1 in the regulation of mitosis. A null mutant or knockdown of HSF1 caused defective mitotic progression. By monitoring chromosomes in living cells, we determined that HSF1 was localized to the centrosome in mitosis and especially to the spindle poles in metaphase. HSF1 was phosphorylated by Plk1 at Ser(216) of the DSGXXS motif during the timing of mitosis and a phospho-defective mutant form of HSF1 inhibited mitotic progression. Phosphorylated HSF1 during spindle pole localization underwent ubiquitin degradation through the SCF(beta-TrCP) pathway. However, binding of HSF1 with Cdc20 stabilized the phosphorylation of HSF1. Moreover, SCF(beta-TrCP)-mediated degradation only occurred when phosphorylated HSF1 was released from Cdc20. HSF1 phosphorylation at Ser(216) occurred in the early mitotic period with simultaneous binding of Cdc20. The interaction of HSF1 with SCF(beta-TrCP) was followed and then the interaction of APC/Cdc20 was subsequently observed. From these findings, it was shown that Plk1 phosphorylates HSF1 in early mitosis and that the binding of phosphorylated HSF1 with Cdc20 and ubiquitin degradation by SCF(beta-TrCP) regulates mitotic progression.
Highlights
Cell division is achieved by the progression through a series of events known as the cell cycle
HSF1À/À murine fibroblast cells (MEF) cells showed reduced phosphorylation of histone H3, a mitosis marker which indicates that heat shock factor 1 (HSF1) is essential to undergo mitotic entry after thymidine double block and release
When compared with HSF1+/+ cells, HSF1À/À MEF cells showed a decreased level of cyclin B1 and securine, suggesting that HSF1 is required for proper mitotic progression
Summary
Cell division is achieved by the progression through a series of events known as the cell cycle. To ensure that the original cell is copied with high fidelity, an elaborate control system using socalled checkpoints is used, preventing cell cycle events from occurring prematurely or in the wrong order. The checkpoint responsible for the appropriate metaphase to anaphase transition during mitosis is called the spindle assembly checkpoint. Its main role is to guarantee that each chromosome is properly attached to the spindle and that the spindle is functional before providing the signal to separate the sister chromatids. A failure to pass on the duplicated genetic material to both daughter cells contributes to cellular transformation, which in turn, might lead to cancer. To ensure proper segregation of chromosomes, mammalian cells undergo mitosis in a tightly controlled manner
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