Loss of p53 and MCT-1 Overexpression Synergistically Promote Chromosome Instability and Tumorigenicity

Kasiappan, Ravi; Shih, Hung-Ju; Chu, Kang-Lin; Chen, Wei-Ti; Liu, Huiping; Huang, Shiu‐Feng; Choy, Chik On; Shu, Chung-Li; Din, Richard; Chu, Jan Show; Hsu, Hsin-Ling

doi:10.1158/1541-7786.mcr-08-0422

Cited by 28 publications

(41 citation statements)

References 35 publications

(51 reference statements)

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“…6B and C). Forming chromosome bridges at telophase stage of MCT-1-p53 cells 35 may delay furrow regression and interrupt mitotic division that cells propagate with cytokinesis failure, resulting in multinucleation (Fig. 5D).…”

Section: Discussionmentioning

confidence: 99%

“…28,[30][31][32] Stimulation of Ras-MAPK signaling cascade in the MCT-1-p53 cells may cause chromosome aberrations, because deactivation of MAPK by the inhibitor reduces polyploidy populations, which bypass the G 2 /M checkpoint in DNA damage response. 35 Thereby, Ras stimulus may be also interrelated to progressively promote polyploidy as the MCT-1-p53 cells constantly propagate or expose to a microtubule poison.…”

Section: Discussionmentioning

confidence: 99%

“…33 Clinical evidence proves that MCT-1 gene expression is induced in a subset of diffuse large B-cell lymphomas and lung carcinomas. 34,35 MCT-1 functions importantly in translation initiation in eukaryotes, 36 which may be related to MCT-1's documented oncogenic impacts on perturbation of kinase signal transduction, DNA damage response and translation regulation. [37][38][39][40] In supporting MCT-1's tumorigenic role, overexpression of MCT-1 transforms normal breast epithelial cells and downregulates p53 expression at both gene and protein levels.…”

Section: The Involvement Of Mct-1 Oncoprotein In Inducing Mitotic Catmentioning

confidence: 99%

“…[37][38][39][40] In supporting MCT-1's tumorigenic role, overexpression of MCT-1 transforms normal breast epithelial cells and downregulates p53 expression at both gene and protein levels. 35,37,41 Moreover, MCT-1 oncogene promotes chromosome abnormalities in the p53-compromised cells upon genotoxic damage and enhances the xenograft tumorigenicity of H1299 (p53-null) lung cancer cells. 35 Though MCT-1 is phosphorylated by CDC2 and ERK kinase in vitro, 42 it is unknown whether MCT-1 is implicated in mitotic function.…”

Section: The Involvement Of Mct-1 Oncoprotein In Inducing Mitotic Catmentioning

confidence: 99%

“…35,37,41 Moreover, MCT-1 oncogene promotes chromosome abnormalities in the p53-compromised cells upon genotoxic damage and enhances the xenograft tumorigenicity of H1299 (p53-null) lung cancer cells. 35 Though MCT-1 is phosphorylated by CDC2 and ERK kinase in vitro, 42 it is unknown whether MCT-1 is implicated in mitotic function. We now demonstrate that MCT-1 is a new centrosomal proto-oncoprotein.…”

Section: The Involvement Of Mct-1 Oncoprotein In Inducing Mitotic Catmentioning

confidence: 99%

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The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

Shih

Chu

et al. 2012

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Involvement Of Mct-1 Oncoprotein In Inducing Mitotic Catmentioning

confidence: 99%

Section: The Involvement Of Mct-1 Oncoprotein In Inducing Mitotic Catmentioning

confidence: 99%

Section: The Involvement Of Mct-1 Oncoprotein In Inducing Mitotic Catmentioning

confidence: 99%

See 3 more Smart Citations

The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

Shih

Chu

et al. 2012

Cell Cycle

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Mutant K‐ras promotes carcinogen‐induced murine colorectal tumourigenesis, but does not alter tumour chromosome stability

Luo¹,

Poulogiannis²,

Ye³

et al. 2010

The Journal of Pathology

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K-ras (KRAS) mutations are observed in around 40% of human colorectal adenomas and carcinomas. Previously, we developed and characterized a strain of transgenic mice with inducible intestinal epithelial expression of K-ras{Val12} via a Cre/LoxP system. To evaluate the influence of mutant K-ras on carcinogen-induced colorectal tumourigenesis, we induced neoplastic alterations in the large intestines of wild-type and K-ras{Val12} mice using the colon-selective carcinogen 1,2-dimethylhydrazine (DMH), which has been widely used to induce colorectal tumours that are histopathologically similar to those observed in humans. K-ras{Val12} expression significantly promoted DMH-induced colorectal tumourigenesis: the average lifespan of the mice decreased from 38.52 ± 1.97 weeks for 40 control mice to 32.42 ± 2.17 weeks for 26 K-ras{Val12} mice (mean ± SEM, p < 0.05) and the abundance of large intestinal tumours increased from 2.27 ± 0.15 per control mouse to 3.85 ± 0.20 in K-ras{Val12} mice (mean ± SEM, p < 0.01). Adenomas from DMH-treated K-ras{Val12} mice showed significantly higher proportions of Ki-67-positive proliferating cells (10.9 ± 0.69%) compared with those from DMH-treated wild-type mice (7.77 ± 0.47%) (mean ± SEM, p < 0.01) and a mild increase in apoptotic nuclei staining for cleaved caspase-3 (1.94 ± 0.21% compared with 1.15 ± 0.14%, mean ± SEM, p < 0.01). In the adenomas from DMH-treated K-ras{Val12} mice, K-ras{Val12} transgene recombination and expression were confirmed, with immunohistochemical evidence of strong Erk/MapK and mild PI3K/Akt pathway activation compared with adenomas from DMH-treated wild-type mice. Microarray hybridization and clustering analysis demonstrated different expression profiles in adenomas from DMH-treated wild-type and DMH-treated K-ras{Val12} mice, indicating involvement of different molecular mechanisms including Erk/MapK and PI3K/Akt signalling in K-ras{Val12}-expressing adenomas. Array-comparative genomic hybridization analysis showed chromosome stability in both cohorts, with only a very few tiny alterations observed in one adenoma from a DMH-treated K-ras{Val12} mouse. Taken together, these data show that mutant K-ras significantly promotes DMH-induced colorectal tumourigenesis, resulting in distinct changes in cell signalling and proliferation, but does not alter chromosome stability in the tumours.

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Constitutive ERK1/2 activation contributes to production of double minute chromosomes in tumour cells

Sun

Quan

Huang

et al. 2014

The Journal of Pathology

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Double minute chromosomes (DMs) are extrachromosomal cytogenetic structures found in tumour cells. As hallmarks of gene amplification, DMs often carry oncogenes and drug-resistance genes and play important roles in malignant tumour progression and drug resistance. The mitogen-activated protein kinase (MAPK) signalling pathway is frequently dysregulated in human malignant tumours, which induces genomic instability, but it remains unclear whether a close relationship exists between MAPK signalling and DMs. In the present study, we focused on three major components of MAPK signalling, ERK1/2, JNK1/2/3 and p38, to investigate the relationship between MAPK and DM production in tumour cells. We found that the constitutive phosphorylation of ERK1/2, but not JNK1/2/3 and p38, was closely associated with DMs in tumour cells. Inhibition of ERK1/2 activation in DM-containing and ERK1/2 constitutively phosphorylated tumour cells was able to markedly decrease the number of DMs, as well as the degree of amplification and expression of DM-carried genes. The mechanism was found to be an increasing tendency of DM DNA to break, become enveloped into micronuclei (MNs) and excluded from the tumour cells during the S/G2 phases of the cell cycle, events that accompanied the reversion of malignant behaviour. Our study reveals a linkage between ERK1/2 activation and DM stability in tumour cells.

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Loss of p53 and MCT-1 Overexpression Synergistically Promote Chromosome Instability and Tumorigenicity

Cited by 28 publications

References 35 publications

The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

Mutant K‐ras promotes carcinogen‐induced murine colorectal tumourigenesis, but does not alter tumour chromosome stability

Constitutive ERK1/2 activation contributes to production of double minute chromosomes in tumour cells

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