Targeting gene expression to tumor cells with loss of wild-type p53 function

Zhu, Jingde; Gao, Baomei; Zhao, Jiangqin; Balmain, Allan

doi:10.1038/sj.cgt.7700091

Cited by 22 publications

(18 citation statements)

References 40 publications

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“…A recent report 11 describes transient transfection experiments exemplifying a novel p53-mediated gene regulation system that could potentially be used in about 50% of human cancers that lack functional p53. 10 The basis for this system is that the majority of cancer cells with mutated p53 and all p53-null cancer cells will be unable to activate a p53-dependent repressor gene cassette allowing a therapeutic gene cassette that is a target for the repressor to express at maximum level in these diseased cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently a novel gene control system based on the ability of p53 to regulate target gene expression has been described. 11 The key feature of this system is that it harnesses p53 present in healthy cells to actively repress therapeutic gene expression. P53-mediated repression of a luciferase gene carried on a plasmid was achieved by cotransfection with a second plasmid carrying a p53-inducible gene encoding a repressor of the promoter driving luciferase expression.…”

Section: Introductionmentioning

confidence: 99%

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Tumour-specific therapeutic adenovirus vectors: repression of transgene expression in healthy cells by endogenous p53

Djeha

Krausz

et al. 2001

Gene Ther

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumour-specific therapeutic adenovirus vectors: repression of transgene expression in healthy cells by endogenous p53

Djeha

Krausz

et al. 2001

Gene Ther

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“…The antibodies against ETS-1, NERF2 [10][11][12] and the two components of NF-κB, p50 and p65, failed to supershift band 2; while the antibody against ETS-2 resulted in a supershifted band (band 3) ( Figure 3E). Further observations strengthening the notion that ETS-2 is the key involved factor suggested from the observation that only ETS-2 consensus effectively competed for the WT binding ( Figure 3B).…”

Section: The Minimal Promoter Of the Hccs1 Gene Spans From -60 To +14mentioning

confidence: 98%

“…The GCCC(GGACTTGCCT) 2 sequence was placed upstream of the minimal promoter of the HSV thymidine kinase promoter (-109 to + 52) and was used as the control for the p53-responsive promoter [11]. An NF-κB-responsive promoter was made by inserting a trimmer of its consensus sequence at the BamHI site of the pGL3-promoter reporter construct.…”

Section: Construction Of Reporter Constructs and Linker-scanner Mutanmentioning

confidence: 99%

“…Binding to its cognate consensus sequence [14] within or near the promoter is essential for the transcriptional activation of the p53's downstream genes [15]. The p53 protein also effectively represses the activity of the promoters devoid of the p53 consensus sequence [11,16,17]. To activate the endogenous p53 pathway of SMMC7721 cells (at the WT p53 status), a well-established p53-inducing agent, Doxorubicin (DOX), was used to treat cells.…”

Section: Nf-κb and P53 Pathways Do Not Play A Role In The Control Of mentioning

confidence: 99%

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Transcription of the putative tumor suppressor gene HCCS1 requires binding of ETS-2 to its consensus near the transcription start site

Zhu

Wang

et al. 2006

Cell Res

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The hepatocellular carcinoma suppressor 1 (HCCS1) gene was identified by both positional cloning from a predominant region of loss of heterozygosity (17p13.3) in liver cancer and by functional screening for genes affecting cell proliferation in large-scale transfection assays. Its overexpression results in inhibition of cell proliferation in cell culture and tumor growth in nude mice. To understand its transcription regulation, the promoter architecture has been dissected in detail. The major start of transcription was mapped by primer extension to a C residue, 177 nucleotides upstream of the ATG codon. By assessing the promoter activity of a set of linker-scanning mutants of the minimal promoter (-60 to +148 region) in a transient transfection assay, we found that the +1 to + 40 region is critical to HCCS1 gene transcription, containing binding sites for transcription factors NF-κB (-21 to +7 and +40 to +26), p53 (+29 to +9) and ETS (+4 to +20 and +23 to +39). Biochemical and molecular analyses revealed that the ETS transcription factors ETS-2 and Elf-1 bind to the two ETS sites in situ and contribute significantly to the transcriptionally active state of the HCCS1 gene, while NF-κB, p53 and two other members of the ETS family (ETS-1 and NERF2) appear to play little role. Our observations provide insight into the mechanistic aspects of HCCS1 transcription regulation.

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Are p53 inhibitors potentially useful therapeutics?

Pietrancosta¹,

Garino²,

Laras³

et al. 2005

Drug Dev. Res.

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The tumor-suppressor protein p53 is an intracellular protein critical in many biochemical cascades leading to cell death via apoptosis pathway or cell survival by arresting the cell cycle. Based on recent studies, which have characterized chemical inhibitors of p53 in the cancer therapy field as well in the pathogenesis of stroke and neurodegenerative disorders, this review concentrates on the development of drugs that inhibit p53 and their possible use as novel strategies for combating neurodegenerative diseases, cancer, and eventually HIV infection. Emphasis is mainly focussed on pifithrin-a derivatives, which appear to be the most efficient p53 inactivators known to date since no such drugs are currently approved. Pifithrin-a antagonises p53 at the post-transcriptional level. The precise mechanism through which their effects are achieved, either by direct interaction of p53 or via indirect binding, remains to be elucidated. Moreover, Pft-a derivatives are cyclized in situ in biological media into their corresponding dehydrated cyclic forms. These cyclic forms, also p53 inactivators, could represent new interesting scaffolds useful in the therapeutic treatment of p53-related disease. Drug Dev Res 65: 43-49, 2005. c 2005 Wiley-Liss, Inc.

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Targeting gene expression to tumor cells with loss of wild-type p53 function

Cited by 22 publications

References 40 publications

Tumour-specific therapeutic adenovirus vectors: repression of transgene expression in healthy cells by endogenous p53

Tumour-specific therapeutic adenovirus vectors: repression of transgene expression in healthy cells by endogenous p53

Transcription of the putative tumor suppressor gene HCCS1 requires binding of ETS-2 to its consensus near the transcription start site

Are p53 inhibitors potentially useful therapeutics?

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