Abstract
Recent evidence indicates that activation of adenosine monophosphate-activated protein kinase (AMPK), a highly conserved sensor and modulator of cellular energy and redox, regulates cell mitosis. However, the underlying molecular mechanisms for AMPKα subunit regulation of chromosome segregation remain poorly understood. This study aimed to ascertain if AMPKα1 deletion contributes to chromosome missegregation by elevating Polo-like kinase 4 (PLK4) expression. Centrosome proteins and aneuploidy were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J) or AMPKα1 homozygous deficient (AMPKα1−/−) mice by Western blotting and metaphase chromosome spread. Deletion of AMPKα1, the predominant AMPKα isoform in immortalized MEFs, led to centrosome amplification and chromosome missegregation, as well as the consequent aneuploidy (34–66%) and micronucleus. Furthermore, AMPKα1 null cells exhibited a significant induction of PLK4. Knockdown of nuclear factor kappa B2/p52 ameliorated the PLK4 elevation in AMPKα1-deleted MEFs. Finally, PLK4 inhibition by Centrinone reversed centrosome amplification of AMPKα1-deleted MEFs. Taken together, our results suggest that AMPKα1 plays a fundamental role in the maintenance of chromosomal integrity through the control of p52-mediated transcription of PLK4, a trigger of centriole biogenesis.
Highlights
The accurate segregation of chromosomes during mitosis is required to correctly transmit genetic information to daughter cells
Proper chromosome segregation during mitosis is facilitated by the attachment of mitotic spindle microtubules to the centrosome, the microtubule-organizing organelle of eukaryotic cells [1], and kinetochore, which is assembled on the chromosomal centromere [2]
We addressed the involvement of a major AMPKα isoform in fibroblasts, AMPKα1, in chromosome segregation by analyzing centrosome amplification in AMPKα1−/− mouse embryo fibroblasts (MEFs)
Summary
The accurate segregation of chromosomes during mitosis is required to correctly transmit genetic information to daughter cells. Proper chromosome segregation during mitosis is facilitated by the attachment of mitotic spindle microtubules to the centrosome, the microtubule-organizing organelle of eukaryotic cells [1], and kinetochore, which is assembled on the chromosomal centromere [2]. Centrosome amplification, with >2 centrosomes per cell, sufficiently drives chromosomal missegregation, leading to aneuploidy. This abnormal number of chromosomes in the cell [7] is associated with chromosomal instability (CIN, gain or loss of whole chromosomes) and consequent genomic destabilization [8,9]. The underlying mechanisms controlling centrosome over-duplication remain weakly understood
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