Mitotic Spindle Checkpoint And The Role Of Aneuploidy

Before mitosis, the mitotic spindle checkpoint allows every chromosome to send a stop signal, arresting cell growth until all the chromosomes are appropriately distributed. Defects in this checkpoint provoke chromosome missegregation and aneuploidy (gain or loss of chromosomes), which can have adverse functional consequences, including cell death, but also cancer. For example, defects in different components of the mitotic spindle checkpoint have consistently been observed in cancer cells, characterized by chromosomal instability (Hanks and Rahman, 2005). Recently, a mouse model was made based on partial inactivation of the gene BubR1, encoding a spindle assembly checkpoint protein. These mice have a median life span of only six months and display a host of premature aging symptoms, including lordokyphosis, cataracts, and muscle atrophy (Baker et al., 2004). They developed aneuploidy from the age of two months onward that increased as the mice aged further. There was a strong correlation between the degree and severity of the chromosome number instability and the onset and progression of the aging phenotypes. Increased apoptosis in several tissues from these animals at one year of age was not found. However, senescence-associated ^-galactosidase activity was high as compared to control mice. This observation of increased cellular senescence in vivo was further supported by an accelerated rate of senescence of embryonic fibroblasts cultured from these mice, which also correlated with the degree of aneuploidy observed in these same cells. Hence, the progressive aneuploidy was assumed to be the underlying cause of both in vitro senescence and the premature aging symptoms in vivo. Interestingly, BubR1 expression declines in tissues of normal mice with age (Baker et al., 2004). Hence, it is conceivable that increased aneuploidy, which has been observed in aging animals, contributes to normal aging as well.

A somewhat unexpected finding in this study was the virtual lack of spontaneous tumors in the mutants, in spite of the fact that aneuploidy is one of the hallmarks of cancer. In this respect, it is possible that the severity of the aneuploidy, while initially promoting the genesis of cancer cells, eventually prevents further tumor progression, similar to the situation in the aforementioned Atm/ Terc mutant mice. This could be a direct effect of ongoing polyploidization or facilitated through the activation of an aneuploidy checkpoint.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment