An Msh2 Conditional Knockout Mouse for Studying Intestinal Cancer and Testing Anticancer Agents

Kucherlapati, Melanie; Lee, Kyeryoung; Nguyen, Andrew A.; Clark, Allan; Hou, Harry; Rosulek, Andrew; Li, Hua; Yang, Kan; Fan, Kunhua; Lipkin, Martin; Bronson, Roderick T.; Jelicks, Linda A.; Kunkel, Thomas A.; Kucherlapati, Raju; Edelmann, Winfried

doi:10.1053/j.gastro.2009.11.009

Cited by 87 publications

(95 citation statements)

References 31 publications

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“…Interestingly, although this missense mutation results in loss of MMR activity, it still retains sensitivity to DNA damage. These results suggest that MSH2 has distinctive functions in MMR activity and chemosensitivity (29). MSH2 and MLH1 have been shown to be required for the activation of various proteins involved in apoptotic pathways such as JNK and c-Abl after cisplatin treatment (30); however, it is not clear whether MutS␣ or MutS␤ or both are involved in the signaling pathways induced by cisplatin or oxaliplatin.…”

Section: Discussionmentioning

confidence: 52%

“…Thus, our results suggest that unrepaired DSBs due to MSH3 deficiency are the direct cause of cell death. However, a recent study has shown that tumors occurring in MSH2-null mice are more resistant to cisplatin and the combination of 5-Fluorouracil plus oxaliplatin than tumors in mice that have MSH2 G674D mutations (29). Interestingly, although this missense mutation results in loss of MMR activity, it still retains sensitivity to DNA damage.…”

Section: Discussionmentioning

confidence: 96%

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MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor

Takahashi¹,

Koi²,

Balaguer

et al. 2011

Journal of Biological Chemistry

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The MSH3 gene is one of the DNA mismatch repair (MMR) genes that has undergone somatic mutation frequently in MMRdeficient cancers. MSH3, together with MSH2, forms the MutS␤ heteroduplex, which interacts with interstrand cross-links (ICLs) induced by drugs such as cisplatin and psoralen. However, the precise role of MSH3 in mediating the cytotoxic effects of ICLinducing agents remains poorly understood. In this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and oxaliplatin, another ICL-inducing platinum drug. Using isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a Tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and oxaliplatin at clinically relevant doses. Interestingly, siRNA-induced down-regulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that this process does not require participation of the canonical MMR pathway. Furthermore, MSH3-deficient cells maintained higher levels of phosphorylated histone H2AX and 53BP1 after oxaliplatin treatment in comparison with MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double strand breaks (DSBs). This role of MSH3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a poly(ADP-ribose) polymerase inhibitor. Moreover, the combination of oxaliplatin and olaparib exhibited a synergistic effect compared with either treatment individually. Collectively, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. These data lay the foundation for the development of effective prediction and treatments for cancers with MSH3 deficiency.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 96%

MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor

Takahashi¹,

Koi²,

Balaguer

et al. 2011

Journal of Biological Chemistry

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“…Thus, we investigated the phenotypic effects of MSH2 inactivation and/or AID activation in hepatocytes in vivo. To disrupt MSH2 and/or express AID specifically in the liver, we crossed MSH2 conditional knockout (Msh2 LoxP/LoxP ) mice (20) and/or AID conditional transgenic (AID cTg) mice (21) with transgenic mice carrying a Cre gene under control of the albumin (ALB) promoter (ALB-Cre; ref. 22).…”

Section: Hepatocellular Carcinoma Develops In Mice With Specific Disrmentioning

confidence: 99%

MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

et al. 2016

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Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFa stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-kBdependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2 À/À AID þ , ALB-MSH2

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“…With regard to the advantage of this mice model over conditional MMR-knockout mice models with a tissuespecific villin promoter, the tumors localize specifically to the cecum, rather than the intestine, although further analyses of coding microsatellite nucleotide repeat gene mutations responsible for tumorigenesis pathway are necessary [45].…”

Section: Discussionmentioning

confidence: 99%

Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras

et al. 2015

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An Msh2 Conditional Knockout Mouse for Studying Intestinal Cancer and Testing Anticancer Agents

Abstract: Background & Aims-Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch Syndromes I & II, and sporadic colorectal cancers (CRCs). Msh2 null mice predominantly develop lymphoma and do not accurately recapitulate the CRC phenotype.

Cited by 87 publications

References 31 publications

MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor

MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor

MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras

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