Connecting mitotic instability and chromosome aberrations in cancer—can telomeres bridge the gap?

Gisselsson, David; Höglund, Mattias

doi:10.1016/j.semcancer.2004.09.002

Cited by 43 publications

(34 citation statements)

References 54 publications

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“…In addition to this, our data suggest an even more complex picture that depends on p53 or p21 checkpoint status ( Figure 6): whereas functional p53 pathway appears to initiate a DNA damage cascade following anaphase bridging and telomere dysfunction (Herbig et al, 2004), absence of this cell-cycle checkpoint leads to endoreduplication (Bunz et al, 1998;Edgar and Orr-Weaver, 2001) and most likely to cytokinesis failure, which ultimately results in centrosome amplification and polyploidy (Gisselsson and Hoglund, 2005). Such supernumerary centrosomes can lead to spindle multipolarity (see Figure 4f), which has been reported in many cancer cell types (Saunders et al, 2000).…”

Section: Discussionmentioning

confidence: 74%

Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells

et al. 2006

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Aneuploidy is a fundamental principle of many cancer cells and is mostly related to defects in mitotic segregation of chromosomes. Many solid tumors as well as some preneoplastic lesions have been shown to contain polyploid chromosome numbers. The exact mechanisms behind whole-genome duplications are not known but have been linked to compromised mitotic checkpoint genes. We now report that the telomere checkpoint plays a key role for polyploidy in colon cancer cells. Telomerase suppression by a dominant-negative mutant of hTERT and consecutive telomere dysfunction in wild-type HCT116 colon cancer cells resulted in only minor stable chromosomal alterations. However, higher ploidy levels with up to 350 chromosomes were found when the cell-cycle checkpoint proteins p53 or p21 were absent. These findings indicate that telomere dysfunction in the absence of cell-cycle control may explain the high frequency of alterations in chromosome numbers found in many solid tumors.

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Section: Discussionmentioning

confidence: 74%

Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells

et al. 2006

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“…These findings suggest that hyperactive Separase results in prematurely segregated chromosomes and lagging chromosomes at anaphase. Increased PCS and formation of anaphase bridges are indicators of chromosomal instability and development of aneuploidy (18).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Separase induces aneuploidy and mammary tumorigenesis

Zhang

Meyer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

137

128

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A neuploidy (aberrant chromosome number) is a hallmark feature of human malignancies (1, 2) and has also been proposed as a necessary event for tumorigenesis (2). Although there have been many proposed hypotheses, there is no general agreement as to why aneuploidy is so highly prevalent in cancer cells, and how it contributes to tumor progression (3, 4). Importantly, if aneuploidy forms an underlying cause of human cancer, it has not been fully substantiated. The mechanisms of aneuploidy also remain a fundamental unresolved problem in cancer biology.To understand how aneuploidy might originate in mammalian tissues, we have focused on the elements that regulate chromosomal segregation, particularly those involved in sister chromatid cohesion and separation, because chromosome missegregation, for example during mitosis, can lead to aneuploidy. A key gene in our analysis is ESPL1, which encodes an endopeptidase called Separase that separates sister chromatids by cleaving cohesin Rad21/Mcd1/Scc1 during the metaphase to anaphase transition. The hypothesis we tested is that hormonal stimulation of the p53-null mouse mammary gland results in misexpression of the ESPL1 gene, thus promoting aneuploidy and breast cancer formation. Dysregulation of the mitotic machinery that helps maintain chromosomal stability in mammary cells can result in aneuploidy and subsequently, cancer formation. We focused on Separase for the following reasons that have important implications for breast cancer: (i) Separase plays a central role in promoting faithful chromosome segregation; (ii) our previous studies strongly indicated that hormonal stimulation of p53-null mice mammary gland results in overexpression of the ESPL1 and Separase protein, which may be a direct cause of aneuploidy (5); and (iii) siRNA-mediated knockdown of Separase and Separase deficient mouse embryonic fibroblasts results in genomic instability (6-8).An evolutionarily conserved protein complex called cohesin and an endopeptidase named Separase play pivotal roles in the accurate segregation of sister chromatids into two daughter cells. Cohesion along the length of the sister chromatids is formed during DNA replication in S phase. Cohesion along the chromosomal arms is removed during prophase and from centromeric regions at the metaphase-to-anaphase transition when Separase is activated after its inhibitory chaperone securin is degraded (9, 10).To understand how aberration in sister chromatid separation may contribute to chromosomal missegregation, we investigated the role of Separase overexpression in mouse mammary cells by using a mammary epithelial transplant model (11) as well as various biochemical and functional assays. Our results indicate that conditional overexpression of Separase alone in mammary epithelial cells with a p53 mutant background is sufficient to induce aneuploidy and tumorigenesis in vitro and in vivo. Results Conditional Expression of Mouse Separase (mSeparase) Results inAneuploidy in Mouse Mammary Epithelial Cells. To examine the direct effect of ...

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“…10,11 A current hypothesis is that telomere dysfunction leads to mitotic disturbances, giving rise to a high rate of chromatin bridges at anaphase and multipolar mitosis (MM) and the triggering of mitotic multipolarity by breakage-fusion-bridge instability is suggested to be one of important mechanisms for the development of chromosomal instability. 12,13 Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and more than 80% of HCC cases are caused by chronic hepatitis B virus (HBV) infection. 14 Telomere length is reported to be shortened in early stages of human hepatocarcinogenesis 15,16 and chromosomal instability induced by shortened telomeres is one of important mechanism of HBV-related hepatocarcinogenesis.…”

Section: Telomericmentioning

confidence: 99%

Telomeric 3′ overhangs in chronic HBV‐related hepatitis and hepatocellular carcinoma

Lee

Choi

et al. 2008

Intl Journal of Cancer

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Telomeric 30 overhang is a key component of telomere structure, but little is known about its role in hepatocarcinogenesis. We examined the 3 0 overhang and telomere length, mRNA levels of hTERT, POT1, TRF1 and cytokeratin 19 (CK19) in 41 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and adjacent non-HCCs of B viral chronic hepatitis/cirrhosis. 3 0 overhang length was positively correlated with telomere length (p < 0.001). In non-HCCs, the 3 0 overhang shortened with increasing age (p 5 0.043). Twenty-six HCCs had shorter and 15 HCCs had longer 3 0 overhangs than the adjacent non-HCCs. The mRNA levels of hTERT, POT1 and TRF1 were upregulated in HCCs than in nonHCCs. HCCs with lengthened 3 0 overhangs expressed higher hTERT mRNA levels than those with shortened 3 0 overhangs, when compared to 3 0 overhangs in non-HCCs (p 5 0.044). POT1 and TRF1 showed no significant difference according to the 3 0 overhangs. HCCs with long 3 0 overhangs had higher mitosis (p 5 0.046) and more frequent multipolar mitosis compared to those with short 3 0 overhangs (p 5 0.034). HCCs with high cytokeratin 19 mRNA levels, a marker for hepatic progenitor cells, had longer 3 0 overhangs than HCCs with low cytokeratin 19 mRNA levels (p 5 0.019). In conclusion, the 3 0 overhang erosion might be closely related to the number of cell divisions in telomerase-negative hepatocytes of chronic hepatitis/cirrhosis. In telomerase-positive HCCs, an altered 3 0 overhang are involved in HBV-related hepatocarcinogenesis and hTERT might be involved in regulation of 3 0 overhang. ' 2008 Wiley-Liss, Inc.

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Connecting mitotic instability and chromosome aberrations in cancer—can telomeres bridge the gap?

Cited by 43 publications

References 54 publications

Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells

Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells

Overexpression of Separase induces aneuploidy and mammary tumorigenesis

Telomeric 3′ overhangs in chronic HBV‐related hepatitis and hepatocellular carcinoma

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