Uniform cell-autonomous tumorigenesis of the choroid plexus by papovavirus large T antigens.

Chen, J D; Dyke, Terry Van

doi:10.1128/mcb.11.12.5968

Cited by 35 publications

(52 citation statements)

References 40 publications

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“…In support of this explanation, tumor growth rate in TgT]2~/TgTTRp53DD mice was similar to that of transgenic mice expressing wild-type T antigen in a similar fraction of CPE cells {tso--6 weeks; Fig. 5; Chen and Van Dyke 1991). These results indicate that tissue-specific expression of p53DD can functionally inactivate wild-type p53 leading to rapid brain tumor progression.…”

Section: Inactivation Of P53 By P53dd Promotes Rapid Brain Tumor Progsupporting

confidence: 66%

“…The plasmid pTTR-p53DD was digested with HindIII, and the 4.7-kb fragment containing the TTRp53DD gene was isolated and microinjected into fertilized mouse eggs (B6D2F 1 x B6D2F 1; Jackson Laboratories, Bar Harbor, ME) as described previously (Chen and Van Dyke 1991;Chen et al 1992). Transgenic offspring were identified by PCR analysis of genomic DNA isolated from tail samples using two sets of primers, one that hybridizes to sequences within the TTR gene promoter region and detects the endogenous TTR gene (internal control) as well as the transgene (5'-TCGCGAATTCGGAGCTTGTGGATCTGT-GTGACGGC-3' and 5'-CTCGAGATCTGGGATTGGGTGT-GTC-3') and a transgene-specific primer set that hybridizes to the TTR intron and to p53DD (5'-CTTTTTGCACCATG-CACCTTTC-3' and 5'-TTGGTCTTCAGGTAGCTGGAGTG-3', respectively).…”

Section: Production and Screening Of Transgenic Micementioning

confidence: 99%

“…The construction of the expression vector containing the truncated T antigen gene pT121 (formerly pLST1137) was described previously (Chen and Van Dyke 1991;Chen et al 1992). The vector used for expression of p53DD (TTR1ExV3) has been described (Wu et al 1996).…”

Section: Plasmidsmentioning

confidence: 99%

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Tissue-specific inactivation of p53 tumor suppression in the mouse.

Bowman¹,

Symonds²,

et al. 1996

Genes Dev.

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The p53 gene is the most frequent target of structural and functional genetic mutations in human cancer. Thus, considerable effort has been devoted to mapping the functional domains of p53 with regard to their impact on tumorigenesis in vivo. Studies have shown that the carboxy-terminal domain of p53 is sufficient for transformation in vitro. To determine whether a transdominant-negative p53 protein could be used to elicit a tissue-specific p53-nuU effect in vivo, we tested whether a carboxy-terminal p53 fragment (amino acids 302-390) could abolish p53-dependent apoptosis in an established tumor progression model. We showed previously that loss of p53-dependent apoptosis accelerates brain tumorigenesis in a transgenic mouse model. Here, we show that the same effect can be elicited by expressing a dominant-negative p53 protein tissue specifically in the presence of wild-type p53. Transgenic mice in which pRb function has been disrupted and that coexpress a p53 carboxy-terminal dominant-negative fragment (p53DD) develop aggressive brain tumors mimicking genetic loss of p53 in this model. Inactivation of endogenous p53, which we show to be complexed with p53DD, results in a reduction in apoptosis and acceleration of tumorigenesis. These studies establish a mechanism for tissue-specific knock out of p53 function in vivo.

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Section: Inactivation Of P53 By P53dd Promotes Rapid Brain Tumor Progsupporting

confidence: 66%

Section: Production and Screening Of Transgenic Micementioning

confidence: 99%

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Tissue-specific inactivation of p53 tumor suppression in the mouse.

Bowman¹,

Symonds²,

et al. 1996

Genes Dev.

Self Cite

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“…We previously established a mouse brain epithelial [choroid plexus epithelium (CPE)] tumor model, TgT 121 , in which choroid plexus carcinoma (CPC) development is initiated by cell-specific transgenic expression of T 121 , an NH 2 -terminal fragment of SV40 T antigen that inactivates pRb and related proteins, p107 and p130 (21). T 121 acutely induces aberrant CPE cell proliferation accompanied by p53-mediated apoptosis and predisposes to aggressive tumor growth, which occurs on p53 inactivation.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of gadd45a Sensitizes Epithelial Cancer Cells to Ionizing Radiation In vivo Resulting in Prolonged Survival

Yang

Hill

et al. 2008

Cancer Research

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Ionizing radiation (IR) therapy is one of the most commonly used treatments for cancer patients. The responses of tumor cells to IR are often tissue specific and depend on pathway aberrations present in the tumor. Identifying molecules and mechanisms that sensitize tumor cells to IR provides new potential therapeutic strategies for cancer treatment. In this study, we used two genetically engineered mouse carcinoma models, brain choroid plexus carcinoma (CPC) and prostate, to test the effect of inactivating gadd45a, a DNA damage response p53 target gene, on tumor responses to IR. We show that gadd45a deficiency significantly increases tumor cell death after radiation. Effect on survival was assessed in the CPC model and was extended in IR-treated mice with gadd45a deficiency compared with those expressing wild-type gadd45a. These studies show a significant effect of gadd45a inactivation in sensitizing tumor cells to IR, implicating gadd45a as a potential drug target in radiotherapy management. [Cancer Res 2008;68(10):3579-83]

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“…However, there is clearly loss of at least one allele. (11,63). Since p53 is inactivated by T antigen in this case, there is no selective pressure for p53 gene loss in these tumors.…”

Section: High Selection For P53 Inactivation During Tumor Evolutionmentioning

confidence: 99%

Selective Inactivation of p53 Facilitates Mouse Epithelial Tumor Progression without Chromosomal Instability

Magrane

Yin

et al. 2001

Molecular and Cellular Biology

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We examined the selective pressure for, and the impact of, p53 inactivation during epithelial tumor evolution in a transgenic brain tumor model. In TgT 121 mice, cell-specific inactivation of the pRb pathway in brain choroid plexus epithelium initiates tumorigenesis and induces p53-dependent apoptosis. We previously showed that p53 deficiency accelerates tumor growth due to diminished apoptosis. Here we show that in a p53 ؉/؉ mice, also with loss of at least one p53 allele and inactivation of p53. Thus, the selective pressure for p53 inactivation, likely based on its apoptotic function, is high. Yet, in all cases, p53 inactivation correlates with progression beyond apoptosis reduction, from dysplasia to solid vascularized tumors. Hence, p53 suppresses tumor progression in this tissue by multiple mechanisms. Previous studies of fibroblasts and hematopoietic cells show that p53 deficiency can be associated with chromosomal instability, a mechanism that may drive tumor progression. To determine whether genomic gains or losses are present in tumors that progress in the absence of p53, we performed comparative genomic hybridization analysis. Surprisingly, the only detectable chromosomal imbalance was partial or complete loss of chromosome 11, which harbors the p53 gene and is thus the selected event. Flow cytometry confirmed that the majority of tumor cells were diploid. These studies indicate that loss of p53 function is frequent under natural selective pressures and furthermore that p53 loss can facilitate epithelial tumor progression by a mechanism in addition to apoptosis reduction and distinct from chromosomal instability.

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Uniform cell-autonomous tumorigenesis of the choroid plexus by papovavirus large T antigens.

Cited by 35 publications

References 40 publications

Tissue-specific inactivation of p53 tumor suppression in the mouse.

Tissue-specific inactivation of p53 tumor suppression in the mouse.

Inactivation of gadd45a Sensitizes Epithelial Cancer Cells to Ionizing Radiation In vivo Resulting in Prolonged Survival

Selective Inactivation of p53 Facilitates Mouse Epithelial Tumor Progression without Chromosomal Instability

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