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Protein Against Mice Aging : BubR1
#1
BubR1 Protein:

Incredible 10-year journey, which had started by the discovery of laboratory raised mouse that get old fast, led scientists to trace the protein that potentially protects animals from cancer and other effects of aging. Although there are still many uncertainties related to that protein called BubR1, there are evidences that the so called protective chromosomes can improve health.

Aneuploidy Causes Cancer?

Jan van Deursen, a biologist from Mayo Clinic in Rochester (Minnesota), who conducts research on tumors, and his colleagues were originally interested in studying the common features of different tumors that are called aneuploidy tumors. Aneuploid cells have an excess or deficiency of chromosomes. Most tumor cells fall under this category, but it remains unclear whether aneuploidy causes cancer indeed.

The Experiment

Van Deursen, along with former student Darren Baker, using genetic modification of mice decreased the production of BubR1 protein that helps cells with chromosome separation after division. After reduction of BubR1 chromosomes can not be properly separated into identical daughter cells, which is why some of the new stations do not have the correct number of chromosomes. Van Deursen, Baker and colleagues have questioned whether tumors will develop in these mice.
To the great surprise, instead of mice full of tumor cells, they have got animals in which the aging process was significantly accelerated. "These mice are obviously strongly different from normal mice," said Baker, who is currently engaged in the biology of aging at the Mayo Clinic. Last year, they found that these mice may help you live longer and healthier by removing old cells, and those cells whose genetic markers indicate aging.

BubR1 gene mutations are extremely rare in humans. This syndrome is characterized by a wide range of aneuploidy, premature aging and increased risk of breast cancer. It seems that the low amount of BubR1 protein is very harmful.

On the other hand, excessive amount of the same protein has a positive effect on health. In the study published in the journal Nature Cell Biology biologists argue that mice, in which the level of BubR1 is highly increased using genetic engineering, are less prone to the development of tumor cells. For example, when normal mice were exhibited to a chemical that causes tumors in the lung and skin, all of them got a cancer. However, only 33% of mice in which extremely high levels of BubR1 are found, developed a cancer under the same conditions. They have found that in these mice the fatal forms of cancer occurred about two years later than normal, and only 15% of the genetically modified mice had died of cancer, compared with 40% of normal.

Mice Run Like Olympians

At the same time, the animals with markedly increased levels of BubR1 lived on average 15% longer than the control group, and they looked like real Olympians on a treadmill, running approximately twice as much as normal mice (200 meters compared to 100 meters). Baker, Van Deursen and colleagues therefore hypothesized that BubR1 does not affect the prolongation of life only by reducing the risk of cancer, and that this hypothesis needs to be checked.

It is of great importance to know why the disorganization of chromosomes can accelerate aging, says Dai Wei, a cell biologist at the University Langone Medical Center in New York. Although aneuploidy seems harmful, studies does not give that kind of results of its effect on animals. "We found that a low level of aneuploidy, such as the one in Van Seurden’s healthy mice, leads to a large number of tumor cells, and not to lower," says Cristina Montagna, molecular geneticist at the Albert Einstein School of Medicine in the Bronx. She and her colleague Jan Vijg collaborate with Van Deursen in study of brain BubR1 in mice. A possible explanation of their findings is that very low as well as very high aneuploidy protect of tumors because the highly aneuploid cells are so damaged that they don’t have the ability of quick division.

Still, there is hope that Van Deursen and colleagues will find a new drug that will slow aging. "We certainly have not found adverse effects of excess amount of BubR1 protein," said Paul Hasty, who studies aging and recovery of DNA at the Center for Health Sciences at the University of Texas. He added that it is necessary to reveal the mechanisms by which BubR1 achieves the desired effect, but this could be a first step in discovering the treatments that could delay aging and possibly prevent the development of cancer.
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#2
BUBR1 and cancer

The original article in this thread explains some recent results concerning the BubR1 mitotic checkpoint protein and ageing. Defects in this protein have been associated with chromosomal instability (CIN) which contributes to cancers with variation in centromere copy number. The article describes results that suggest high levels of BubR1 confer a survival advantage in mouse models of lung and skin cancer. However the biomedical literature contains several examples in which elevated BubR1 appears to be associated with tumour development and poor prognosis, so there is some confusion as to the role of this protein in cancer which requires further research before it can be fully elucidated.

For example, in a study on human urothelial bladder carcinomas, it was found that in tumours in which there was high expression of BUBR1, there was also CIN, DNA aneuploidy, and centrosome amplification, associated with advanced pathological stage and poor outcomes including tumour recurrence and disease progression. Similarly to bladder cancer, in glioblastoma (GBM) cell lines and tumour samples, increased expression of BUB and BUBR1 was also observed. Upon reduction of BUBR1 expression with siRNA, there was decreased cell proliferation and colony formation and sensitisation of cells to γ-irradiation. Meanwhile studies on hepatocellular carcinoma (HCC) suggested that while high levels of BUBR1 was not uniform across HCCs, being overexpressed in about 45% HCCs, however where it was observed it correlated with increased tumour size and similarly to bladder cancer, higher histological grade, advanced pathology, increased recurrence and lower survival rates. Higher BUBR1 was also associated with p53 expression and with high levels of the proliferation marker Ki67 in HCC tissues.

Clearly on-going research on BUBR1 and cancer and ageing is essential.

Sources

LIU, A. et al., 2009. The clinicopathological significance of BUBR1 overexpression in hepatocellular carcinoma. Journal of clinical pathology, 62(11), pp. 1003-1008

MORALES, A.G. et al., 2013. BUB1 and BUBR1 inhibition decreases proliferation and colony formation, and enhances radiation sensitivity in pediatric glioblastoma cells. Springer Verlag.

YAMAMOTO, Y. et al., 2007. Overexpression of BUBR1 is associated with chromosomal instability in bladder cancer. Cancer genetics and cytogenetics, 174(1), pp. 42-47
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