Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect

Campbell, Margaret L.; Wang, Y; Andrew, Susan E.; Liu, Y

doi:10.1038/sj.onc.1209277

Cited by 43 publications

(31 citation statements)

References 21 publications

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“…59,85,86 By spectral karyotype, the B-cell lineage tumors of MSH6-deficient mice did not bear chromosomal translocations, although chromosomal aneuploidies were common. Similar abnormalities have been observed in embryonic fibroblasts from mice deficient in MSH2 82,87 and in colon cancers in MMR-deficient mice and humans with microsatellite instability. 61,62 Array comparative genomic hybridization, with its greater resolution, did reveal chromosomal regions that were amplified or deleted, and some of these were common to two or three of the four tumors examined (Table 3).…”

Section: Msh6supporting

confidence: 59%

Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability

Peled

Sellers

Iglesias-Ussel

et al. 2010

The American Journal of Pathology

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Most human B-cell non-Hodgkin's lymphomas arise from germinal centers. Within these sites, the mismatch repair factor MSH6 participates in antibody diversification. Reminiscent of the neoplasms arising in patients with Lynch syndrome III, mice deficient in MSH6 die prematurely of lymphoma. In this study, we characterized the B-cell tumors in MSH6-deficient mice and describe their histological, immunohistochemical, and molecular features, which include moderate microsatellite instability. Based on histological markers and gene expression , the tumor cells seem to be at or beyond the germinal center stage. The simultaneous loss of MSH6 and of activation-induced cytidine deaminase did not appreciably affect the survival of these animals , suggesting that these germinal center-like tumors arose by an activation-induced cytidine deaminase-independent pathway. We conclude that MSH6 protects B cells from neoplastic transformation by preserving genomic stability.

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Section: Msh6supporting

confidence: 59%

Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability

Peled

Sellers

Iglesias-Ussel

et al. 2010

The American Journal of Pathology

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“…Previous studies showed that deficiency in Msh2 leads to chromosomal aneuploidy (22). Hence, we investigated whether the accelerated lymphomagenesis observed in Msh2 Ϫ/Ϫ E c-myc mice may be caused by gross chromosomal aberrations (i.e., aneuploidy/chromosomal translocations).…”

Section: Inactivation Of the Myc-p53 Apoptotic Pathway Is Reduced In mentioning

confidence: 99%

Msh2-dependent DNA repair mitigates a unique susceptibility of B cell progenitors to c-Myc -induced lymphomas

Nepal

Kolaj

et al. 2009

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

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C-Myc is one of the most common targets of genetic alterations in human cancers. Although overexpression of c-Myc in the B cell compartment predisposes to lymphomas, secondary mutations are required for disease manifestation. In this article, we show that genetic deficiencies causing arrested B cell development and accumulation of B cell progenitors lead to accelerated lymphomagenesis in E c-myc transgenic mice. This result suggests that B cell progenitors are more prone than their mature counterparts to developing secondary oncogenic lesions that complement c-Myc in promoting transformation. To investigate the nature of these oncogenic lesions, we examined E c-myc mice deficient in mismatch repair function. We report that Msh2 ؊/؊ E c-myc and Msh2 G674A/G674A E c-myc mice rapidly succumb to pro-B cell stage lymphomas, indicating that Msh2-dependent mismatch repair function actively suppresses c-Myc-associated oncogenesis during early B cell development.apoptosis ͉ mismatch repair ͉ oncogenesis ͉ p53

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“…Genetic and biochemical studies indicate that Msh2 is a critical component of all MMR complexes and, consequently, Msh2-null mutants are predicted to completely the lack MMR response (17,18). Significantly, loss or mutation of mammalian Msh2 increases the probability of developing certain types of tumors (19).…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

Aoi

Endo

Kadomatsu

et al. 2014

Molecular Cancer Research

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Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.

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Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect

Cited by 43 publications

References 21 publications

Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability

Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability

Msh2-dependent DNA repair mitigates a unique susceptibility of B cell progenitors to c-Myc -induced lymphomas

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

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