Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer.

Levine, Douglas S.; Sanchez, Carissa A.; Rabinovitch, Peter S.; Reid, Brian J.

doi:10.1073/pnas.88.15.6427

Cited by 119 publications

(72 citation statements)

References 31 publications

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“…Other reports also support the idea that mutations in mitotic checkpoint proteins can cause genomic instability and in rare cases give rise to cancer (36,39). Because tetraploidy is frequently an intermediate step for progression to aneuploidy, it is particularly interesting that T antigen has already been shown to induce tetraploid DNA content in both permissive and nonpermissive cells (37,40). We found that Parental U2OS or U2OS lines stably expressing T antigen or the dl89 -97 mutant were treated with nocodazole for 48 h, and the extent of endoreduplication was determined by fluorescence-activated cell sorting analysis.…”

Section: Discussionmentioning

confidence: 75%

“…The interaction of Bub1 and T antigen may explain several previous reports that demonstrated that T antigen is able to induce aneuploidy and genetic instability, giving rise to both structural and numerical chromosome aberrations (14)(15)(16)(17)37). It had been proposed that this instability was most likely caused by the ability of T antigen to interact with and inactivate the p53 protein.…”

Section: Discussionmentioning

confidence: 84%

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Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1

Cotsiki

Lock

Cheng

et al. 2004

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

104

112

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The mitotic spindle checkpoint protein Bub1 has been found to be mutated at low frequency in certain human cancers characterized by aneuploidy. Simian virus 40 large T antigen efficiently immortalizes rodent cells and occasionally transforms them to tumorigenicity. T antigen can also cause genomic instability, inducing chromosomal aberrations and aneuploidy. Here, we report an interaction between Bub1 and T antigen. T antigen coimmunoprecipitates with endogenous Bub1 and Bub3, another component of the spindle checkpoint complex. Genetic analysis demonstrates that the interaction of T antigen with Bub1 is not required for immortalization but is closely correlated with transformation. T antigen induces an override of the spindle checkpoint dependent on Bub1 binding. This interaction with proteins of the spindle checkpoint machinery suggests another role for T antigen and provides insight into its ability to cause chromosomal aberrations, aneuploidy, and transformation.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 84%

Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1

Cotsiki

Lock

Cheng

et al. 2004

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

104

112

View full text Add to dashboard Cite

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“…In 1991 Levine et al reported that formation of tetraploid intermediates is associated with the development of cells with more than four centrioles in the development of pancreatic cancer in transgenic mice expressing the simian virus 40 tumor antigen (30), which is one of the viral oncoproteins known to interact with p53 (31). Furthermore, Levine et al observed that in ulcerative colitis with dysplasia or cancer genomic instability and clonal evolution of aneuploid cells were associated with malignancy progression (32).…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus Infection, Centrosome Aberration, and Genetic Stability in Cervical Lesions

et al. 2001

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DNA replication and centrosome duplication have to be strictly synchronized to guarantee genomic stability. p53, pRb, cyclin E, and cyclin A are reported to be involved in the synchronizing process. We investigated the relationship between papillomavirus infection, centrosome aberration and aneuploidy during genesis of cervical carcinoma. The number of centrosomes found in cells from normal cervical epithelium (n ‫؍‬ 5), condyloma acuminata (n ‫؍‬ 5), cervical intraepithelial neoplasia (CIN) I, II, and III (n ‫؍‬ 14) and invasive cervical carcinoma (n ‫؍‬ 5) was analyzed by ␥ tubulin immunofluorescence staining. The nuclear DNA content was investigated by image cytometry and human papillomavirus (HPV) infection was determined by polymerase chain reaction. Normal epithelia and condyloma acuminata showed cells with one or two centrosomes, whereas CIN lesions showed cells with an increasing number of centrosomes. This abnormality was found to be lowest in CIN I lesions, increased with advancing grade of CIN and was highest in lesions of invasive carcinomas. In parallel, an increasing number of cells with aberrant DNA content was seen. All carcinomas and all except one of the CIN III lesions showed aneuploidy. Three CIN II cases were aneuploid and two cases with CIN I were tetraploid. Normal epithelia and condyloma acuminata showed diploidy. All invasive carcinomas and lesions with CIN were positive for high-risk HPV types 16, 18, or 31, except one invasive carcinoma and one CIN II lesion positive for universal primers only. Three condyloma acuminata were HPV 16-positive and one HPV 6-positive.The results suggest that high-risk HPV infection is correlated to a progressive numerical disturbance of centrosome replication followed by progressive chromosomal aberrations in CIN lesions and invasive carcinomas.

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“…Increased G2/M DNA content has been previously described in pancreatic cancer models. For example, pancreatic tumors develop in transgenic mice expressing the SV40 Tantigen under the control of the elastase I promoter (Levine et al, 1991). In these animals, the 4N state is associated with increased number of centrioles per cell.…”

Section: Agn193198 -An Effective Inhibitor Of Pancreatic Cell Prolifementioning

confidence: 99%

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)-or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR-or RXR receptorselective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclindependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.

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Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer.

Cited by 119 publications

References 31 publications

Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1

Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1

Human Papillomavirus Infection, Centrosome Aberration, and Genetic Stability in Cervical Lesions

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

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