X-Message-Number: 24361
Date: Thu, 8 Jul 2004 20:55:16 -0700 (PDT)
From: Doug Skrecky <>
Subject: Bubr1 related abstracts

Nature Genetics 36, 744 - 749 (2004)
BubR1 insufficiency causes early onset of aging-associated phenotypes and
infertility in mice
  Faithful segregation of replicated chromosomes is essential for
maintenance of genetic stability and seems to be monitored by several
mitotic checkpoints. Various components of these checkpoints have been
identified in mammals, but their physiological relevance is largely
unknown. Here we show that mutant mice with low levels of the spindle
assembly checkpoint protein BubR1 develop progressive aneuploidy along
with a variety of progeroid features, including short lifespan, cachectic
dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired
wound healing. Graded reduction of BubR1 expression in mouse embryonic
fibroblasts causes increased aneuploidy and senescence. Male and female
mutant mice have defects in meiotic chromosome segregation and are
infertile. Natural aging of wild-type mice is marked by decreased
expression of BubR1 in multiple tissues, including testis
and ovary. These results suggest a role for BubR1 in regulating aging and
infertility.

Nature Genetics 36, 672 - 674 (2004)
Aging counts on chromosomes
  The acquisition of an abnormal number of chromosomes is a hallmark of
many human cancers. A new study indicates that unequal segregation of
genetic material to daughter cells during cell division can also lead to
premature senescence and accelerated onset of a variety of aging
phenotypes.

Cancer Cell. 2003 Dec;4(6):483-97.
Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring
of chromosomal instability.
  In this study, we show that the formation of polyploidy following
sustained mitotic checkpoint activation appears to be preceded by the
ubiquitin-dependent proteolysis of hBubR1. In addition, the level of
hBubR1 is significantly reduced not only in polyploid cells created by
sustained mitotic spindle damage, but also in 21 (31.3%) of 67 human colon
adenocarcinomas tested. Importantly, the introduction of hBubR1 triggers
the apoptosis of polyploid cells formed by aberrant exit from mitosis and
inhibits the growth of tumors established with these cells in athymic
nude mice. These results suggest that hBubR1-mediated apoptosis prevents
the propagation of cells that breach the mitotic checkpoint and that the
control of hBubR1 protein level is an important factor in the acquisition
of preneoplastic polyploidy.

J Biol Chem. 2004 Feb 13;279(7):5306-13. Epub 2003 Nov 22.
Vascular smooth muscle polyploidization as a biomarker for aging and its
impact on differential gene expression.
  Polyploidy is characterized by a greater than diploid content of DNA in
a cell. Previous measurements of ploidy level in different organs of
humans and rodents, including the aorta, indicated an increase in old
versus young. We hypothesized that aortic vascular smooth muscle
polyploidy is a biomarker for aging and that the augmented DNA dosage
affects selective gene-specific transcript expression. Our results
demonstrate that tetraploidy increases exponentially over the life span
of the animal, serving as an indicator of age. Approximately 60% of the
vascular smooth muscle cells in the thoracic aorta of 36-month-old Brown
Norway rats are tetraploid compared with 8% in their 3-month-old
counterparts. Microarray analysis and reverse transcriptase-PCR was
performed with mRNA isolated from sorted diploid (2N) and tetraploid (4N)
vascular smooth muscle cells from old rats to identify differentially
expressed transcripts. For the majority of detectable transcripts, an
increase in DNA content led to a proportional increase in mRNA. A select
group of transcripts, however, were reduced in tetraploid compared with
diploid cells. These mRNAs correspond to guanine deaminase, to the
matrix proteins rat glypican 3 (OCI-5) and decorin, as well as to the
inflammation-associated transcripts, insulin-like growth factor-binding
protein 6, macrophage inflammatory protein 2 precursor, macrophage
galactose N-acetylgalactoseamine-specific lectin, and complement
component C4. Our study is the first to describe aortic ploidy level as a
biomarker for aging and to indicate that changes associated with
increased DNA content per cell may selectively suppress the expression of
specific genes.

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