CTS1: a p53-derived chimeric tumor suppressor gene with enhanced in vitro apoptotic properties.

Conseiller, Emmanuel; Debussche, Laurent; Landais, Didier; Venot, Corinne; Maratrat, Michel; Sierra, Véronique; Tocqué, Bruno; Bracco, Laurent

doi:10.1172/jci1140

Cited by 30 publications

(32 citation statements)

References 44 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several such p53 variants have been described, including p53(14/19) and p53(22/23) with amino acid substitutions in the MDM2 binding domain (16), p53(d 13 -19) with a deletion in the MDM2 binding site (15), and the chimeric p53 analogue CTS1 in which the entire NH 2 -terminal domain comprising the MDM2 binding site was replaced by the herpes simplex virus VP16 transactivation domain (21). The variants p53(14/19), p53(d 13 -19), and CTS1 have already been introduced into cancer cells with high MDM2 expression by means of replication-deficient adenovirus vectors and shown to confer growth inhibition and apoptosis induction in these cells (22 -25).…”

Section: Resultsmentioning

confidence: 99%

Conditionally replicative adenovirus expressing degradation-resistant p53 for enhanced oncolysis of human cancer cells overexpressing murine double minute 2

Beusechem

Doel

Gerritsen

2005

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Conditionally replicative adenoviruses (CRAd) are under investigation as anticancer agents. Previously, we found that the CRAd Ad#24-p53, expressing the p53 tumor suppressor protein from its genome, more effectively killed most human cancer cells than did its parent Ad#24. However, a minority of cancer cell lines poorly responded to the oncolysis-enhancing effect of p53. Here we show that refractory cell lines expressed high levels of the major negative p53 regulator murine double minute 2 (MDM2).

show abstract

Section: Resultsmentioning

confidence: 99%

Conditionally replicative adenovirus expressing degradation-resistant p53 for enhanced oncolysis of human cancer cells overexpressing murine double minute 2

Beusechem

Doel

Gerritsen

2005

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…To explore this possibility, we compared inhibition of colony formation by p53 with CTS1, a chimeric p53 molecule (Conseiller et al, 1998). CTS1 is resistant to inactivation by MDM2 since it has the VP16 activation domain in the place of the p53 activation domain that interacts with MDM2.…”

Section: Tumour Cell Linesmentioning

confidence: 99%

p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

et al. 1999

View full text Add to dashboard Cite

The p53 tumour suppressor is frequently inactivated in human tumours. One form of inactivation results from overexpression of MDM2, that normally forms a negative auto-regulatory loop with p53 and inhibits its activity through complex formation. We have investigated whether disrupting the MDM2-p53 complex in cells that overexpress MDM2 is sucient to trigger p53 mediated cell death. We ®nd that expression of a peptide homologue of p53 that binds to MDM2 leads to increased p53 levels and transcriptional activity. The consequences are increased expression of the downstream eectors MDM2 and p21, inhibition of colony formation, cell cycle arrest and cell death. There is also a decrease in E2F activity, that might have been due to the known physical and functional interactions of MDM2 with E2F1/DP1. However, this decrease is p53 dependent, as are also colony formation, cell cycle arrest and cell death. These results show that a peptide homologue of p53 is sucient to induce p53 dependent cell death in cells overexpressing MDM2, and support the notion that disruption of the p53-MDM2 complex is a target for the development of therapeutic agents.

show abstract

“…3 We previously reported that Ad-CTS-1 kills human gliomas independent of their endogenous p53 status and more efficiently than wild-type p53. The biochemical pathways mediating CTS-1-induced cell death remained obscure, but did not involve death ligand/receptor interactions, caspase activation or altered BCL-2 family protein expression.…”

Section: Discussionmentioning

confidence: 98%

“…The carboxyterminal self-inhibitory domain of p53 is deleted. 3 Adenoviral CTS-1 gene transfer induces growth arrest and loss of viability in p53 wild-type and p53 mutant human malignant cell lines better than wildtype p53 4 as well as in mouse-double-minute-2 (MDM-2)-overexpressing breast cancer cells. 5 Since the best-established function of p53 is to act as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we here assessed whether specific differences in the modulation of gene expression are responsible for the superior antitumor properties of CTS-1 compared with wild-type p53 using cDNA microarray analysis.…”

Section: Introductionmentioning

confidence: 99%

PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells

et al. 2005

View full text Add to dashboard Cite

Chimeric tumor suppressor-1 (CTS-1) is based on the sequence of p53 and was designed as a therapeutic tool resisting various mechanisms of p53 inactivation. We previously reported that an adenovirus expressing CTS-1 (Ad-CTS-1) has superior cell deathinducing activity in glioma cells compared with wild-type p53. Here, we used cDNA microarrays to detect changes in gene expression preferentially induced by Ad-CTS-1. The putative serin threonine kinase, PCTAIRE3, and the quinone oxireductase, PIG3, were strongly induced by Ad-CTS-1 compared with wild-type p53. An adenoviral vector encoding PCTAIRE3 (Ad-PCTAIRE3) induced growth arrest and killed a minor proportion of the glioma cells. Ad-PIG3 alone affected neither growth nor viability. However, coinfection with Ad-PCTAIRE3 and Ad-PIG3 resulted in enhanced growth inhibition compared with Ad-PCTAIRE3 infection alone. Ad-CTS1, Ad-PCTAIRE3 or Ad-PIG3 induced the formation of free reactive oxygen species (ROS). However, the prevention of ROS formation induced by Ad-PCTAIRE3 and Ad-CTS-1 did not block growth arrest and cell death, suggesting that ROS formation is not essential for these effects. Altogether, these data identify PCTAIRE3 as one novel growth-inhibitory and deathinducing p53 response gene and suggest that changes in the expression of specific target genes contribute to the superior antiglioma activity of CTS-1.

show abstract

CTS1: a p53-derived chimeric tumor suppressor gene with enhanced in vitro apoptotic properties.

Cited by 30 publications

References 44 publications

Conditionally replicative adenovirus expressing degradation-resistant p53 for enhanced oncolysis of human cancer cells overexpressing murine double minute 2

Conditionally replicative adenovirus expressing degradation-resistant p53 for enhanced oncolysis of human cancer cells overexpressing murine double minute 2

p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells

Contact Info

Product

Resources

About