An essential role for p73 in regulating mitotic cell death.
The molecular mechanisms regulating cell death during mitosis are poorly understood. We show here a critical role for p73, but not p53, in regulating mitotic cell death induced by various means. Prolonged mitotic arrest and the activation of spindle checkpoint are required for mitotic death, which occurs before mitotic exit and which can be ameliorated by accelerated mitotic exit. Absence or silencing of p73 expression abrogated mitotic death without accelerating mitotic exit, and was independent of BubR1 and Mad2, the loss of which promotes mitotic exit. However, the absence of p73 reduced mitotic death by compromising the expression of the proapoptotic BH3-only protein Bim and thereby affecting cytochrome c release and caspase activation. p73 was found to induce bim expression through direct binding to regulatory elements in intron 1. Congruently, mitotic cell death was rescued to similar extents by silencing either bim or p73 expression. Taken together, the data show an important role for the p73-Bim axis in regulating cell death during mitosis that is independent of p53.
Toh
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WH
Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore.
Nam
S Y
SY
Sabapathy
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K
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017239:Paclitaxel