Abstract
BubR1 mitotic checkpoint kinase monitors attachment of microtubules to kinetochores and links regulation of the chromosome-spindle attachment to mitotic checkpoint signaling. Defects in BubR1-mediated signaling severely perturb checkpoint control and are linked to diseases such as cancer. Studies using BubR1 mouse models suggest that BubR1 activities prevent premature aging and infertility. In this study, we show that BubR1 depletion in human adipose-derived mesenchymal stem cells (ASCs) precedes loss of the differentiation potential and induction of replicative senescence. These effects occur independently of p16(INK4A) expression and may involve DNA methylation. Our results reveal a new and unsuspected feature of BubR1 expression in regulation of adult stem cell differentiation.
Highlights
BubR1 is a critical component of the mitotic checkpoint that is localized to kinetochores
BubR1 levels decline during replicative senescence in human adipose-derived stem cells (hASCs)
Vol 41(12), 873-879, 2009 human adult stem cells, we isolated human adipose-derived stem cells from the fatty portion of liposuction aspirates. hASCs, which may differentiate into adipocytes, chondrocytes, osteocytes, and neuronal cells, were positive for known mesenchymal markers (e.g., CD44, CD73 and CD105), but negative for CD45, as reported previously (Noel et al, 2008)
Summary
BubR1 is a critical component of the mitotic checkpoint that is localized to kinetochores. Studies show that BubR1 disruption results in loss of checkpoint control, chromosomal instability (caused by premature anaphase), and/or early onset of malignancy (Cahill et al, 1998; Taylor et al, 1998; Baker et al, 2004; Dai et al, 2004). BubR1-mutant mice showed defective chromosome segregation in meiosis and were infertile (Baker et al, 2004). Gradual reduction of BubR1 expression in mouse embryonic fibroblasts promotes cellular senescence. These observations indicate that normal BubR1 expression prevents early aging and infertility in mice. Whether and how BubR1 influences the life span and senescence in human adult stem cells and primary cells is not yet known
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