Transactivation by temperature-dependent p53 mutants in yeast and human cells

Slováčková, Jana; Grochová, Diana; Navrátilová, Jarmila; Šmarda, Jan; Šmardová, Jana

doi:10.4161/cc.9.11.11808

Cited by 15 publications

(18 citation statements)

References 23 publications

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“…LNCaP cells displayed even greater p53 protein heterogeneity with many cells lacking detectable protein expression. As the p53 mutation reported for IGR-CaP1 cells, Y126C [23], has been shown to lack transcriptional activity [28], it was surprising that the p53 target, p21, was coordinately upregulated in IGR-CaP1 cells (Figure 4A). However, further investigation using ICC revealed that p21 was localized to the cytoplasm in the majority of IGR-CaP1 cells (only 19/394 cells positive for nuclear p21 expression) (Figure 5, representative high magnification confocal image).…”

Section: Resultsmentioning

confidence: 89%

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector

Kaliberov

Sohn

et al. 2017

Oncotarget

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While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/SCID/IL2Rg -/− (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.

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Section: Resultsmentioning

confidence: 89%

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector

Kaliberov

Sohn

et al. 2017

Oncotarget

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“…To limit the influence of genetic background, we prepared several H1299 cell line variants inducibly expressing various forms of p53: the positive control expressing p53wt, the negative control expressing fully inactive hot-spot mutant R175H, and td mutants P98A, A159V, S215G, Y220C, and Y234C. Temperature-dependency and transactivation abilities of the td p53 mutants were previously characterized both in yeast and human cells [14,15]. The P98A mutant behaved as cold-sensitive, retaining lower activity at decreased temperature than at physiological temperature.…”

Section: Resultsmentioning

confidence: 99%

“…p21) rather than pro-apoptotic genes (e.g. bax) [15]. The p21 gene possesses high affinity promoter, whereas the bax promoter has low affinity for p53 [22].…”

Section: Discussionmentioning

confidence: 99%

“…Stable transfectants were selected with 500 μg/ml Geneticin sulfate G418 (Gibco) and 5 μg/ml Blasticidin S HCl (Invitrogen). Expression of p53 in transfected cells was induced by tetracycline (1 μg/ml) [15]. The cells were treated with R-roscovitine (6-(benzylamino)-…”

Section: Methodsmentioning

confidence: 99%

“…Their function can be restored in permissive temperature. In our earlier studies, we investigated functional state, especially transactivation activity, of td p53 mutants in yeast [14] and in human non-small cell lung carcinoma H1299 cells [15]. In the present study, we analyzed the way how various td p53 variants affect response of H1299 cells to roscovitine.…”

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confidence: 99%

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Roscovitine-induced apoptosis of H1299 cells depends on functional status of p53

Slováčková¹,

Šmarda²,

Šmardová³

2012

neo

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Roscovitine, an inhibitor of cyclin-dependent kinases, is promising anticancer agent. Its antiproliferative and cytotoxic effects can be mediated by the p53 signaling pathway. To define the role of p53 in roscovitine-induced cell response, we prepared H1299/p53 cell lines inducibly expressing specific variants of p53 (p53wt and hotspot R175H, temperature-dependent P98A, A159V, S215G, Y220C, Y234C mutants). In the presence of roscovitine, each cell line variant behaved in specific way reflecting activity of the p53 protein. Roscovitine decreased production of the cell cycle inhibitor p21 and induced apoptosis. This effect was the most efficient in cells expressing p53wt protein with full activity. The cell expressing partially and conditionally active p53 mutants responded to roscovitine less efficiently. The cells expressing p53 mutants A159V and Y234C were very sensitive to roscovitine but their response was clearly temperature-dependent. The cells expressing P98A, S215G and Y220C p53 mutants exhibited only weak sensitivity to roscovitine and underwent apoptosis in low frequency. In principle, each td p53 mutant responded to roscovitine in distinct way. We showed clearly that the impact of roscovitine on H1299 cells depends on functional status of p53 they produce. This suggests that patients with tumors exhibiting specific p53 variants can benefit from the roscovitine therapy.

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Current awareness on yeast

2010

Yeast

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Yeast Yeast 20I0; 27: I07I-I079 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: I0.I002/yea.I724 Current awareness on yeast(5 weeks journals -Search completed at 13th. Oct. 2010) In order to keep subscribers up-to-date with the latest developments in their field, this current awareness service is provided by John Wiley & Sons and contains newly-published material on yeasts. Each bibliography is divided into I0 sections. I Reviews; 2 General; 3 Biochemistry; 4 Biotechnology; 5 Cell Biology; 6 Gene Expression; 7 Genetics & Genomics; 8 Physiology; 9 Medical Mycology; I0 Recombinant DNA Technology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

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Transactivation by temperature-dependent p53 mutants in yeast and human cells

Cited by 15 publications

References 23 publications

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector

Roscovitine-induced apoptosis of H1299 cells depends on functional status of p53

Current awareness on yeast

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