Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites

Hua, Qian; Wang, Ting; Naumovski, Louie; Lopez, Charles D.; Brachmann, Rainer K.

doi:10.1038/sj.onc.1205974

Cited by 120 publications

(129 citation statements)

References 44 publications

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“…Only experiments with high levels of p53 showed a significant increase of DNA binding (Figure 1). These data are supported by recent in vivo analyses indicating that p53 binding and transactivation via the bax response element is very weak compared to WAF or mdm2 (Inga et al, 2002;Qian et al, 2002). Furthermore, both studies showed that the transcriptional activation of WAF1 promoter by p53 is two to five times stronger than for mdm2 promoter, supporting the results of our in vitro studies.…”

Section: Published Online 7 June 2004supporting

confidence: 81%

Versatile analysis of multiple macromolecular interactions by SPR imaging: application to p53 and DNA interaction

et al. 2004

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The greatest challenge in the postgenomic era is the description of proteome interactions, such as protein-protein or protein-DNA interactions. Surface plasmon resonance (SPR) is an optical technique in which binding of an analyte to the surface changes the refractive index at the surface/solution interface. Molecular interactions are analysed in real time without a labeling step. Currently, the limit to SPR imaging is the small number of reactions that can be simultaneously analysed. Using a novel grafting technology and a new imaging system, we increased the throughput of SPR imaging. The interaction between p53 and DNA was chosen as a paradigm for validation of this assay. Using a tagged DNA methodology, we simultaneously targeted multiple DNA sequences on a single chip. The interaction between p53 and these DNA sequences was monitored by SPR imaging. Qualitative and quantitative analysis provides results similar to those obtained with conventional technologies.

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Section: Published Online 7 June 2004supporting

confidence: 81%

Versatile analysis of multiple macromolecular interactions by SPR imaging: application to p53 and DNA interaction

et al. 2004

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“…At present, little is known about how the epigenetic network interacts with other transcriptional machineries to regulate gene expression in mammalian cells. In the past, p53-binding motifs with GC rich features were observed in several gene promoters including EGFR, Killer/DR4, RB and TGF-a (Qian et al, 2002). However, there are fundamental questions that need to be answered.…”

Section: Discussionmentioning

confidence: 99%

WTH3 is a direct target of the p53 protein

Tian

Wang

2007

Br J Cancer

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Previous results showed that overexpression of the WTH3 gene in multidrug resistance (MDR) cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. The WTH3 gene promoter was found to be differentially regulated in paired MDR vs non-MDR MCF7 cells owing to epigenetic modifications and transcription factor modulations. To understand further the mechanisms that govern WTH3's differential expression, we uncovered a p53-binding site in its promoter, which indicated that WTH3 could be regulated by the p53 gene. This hypothesis was then tested by different strategies. The resulting data revealed that (1) the WTH3 promoter was upregulated by the p53 transgene in diverse host cells; (2) there was a correlation between WTH3 expression levels and p53 gene status in a cell line panel; (3) a WTH3 promoter region was directly targeted by the p53 protein in vitro and in vivo. In addition, overexpression of the WTH3 gene promoted the apoptotic phenotype in host cells. On the basis of these findings, we believe that the negative role played by the WTH3 gene in MDR development is through its proapoptotic potential that is regulated by multiple mechanisms at the transcription level, and one of these mechanisms is linked to the p53 gene.

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“…This "half-site" sequence is separated from another half-site by 0 to 13 bp in most cases. However, a number of known p53 targets are regulated through a broad range of degenerate sequences (66), making the identification of functional p53REs potentially problematic. In order to individually confirm p53 association with selected promoters, we first identified potential p53REs in the vicinity of identified CGIs.…”

Section: Resultsmentioning

confidence: 99%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.The tumor microenvironment is a major factor influencing tumor growth, metastatic potential, and response to chemotherapeutic drugs and radiation therapy (7). The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of key enzymes in anaerobic glycolysis and proangiogenic factors (i.e., vascular endothelial growth factor), aiding cells in adapting to a low-oxygen environment (15). Thus, a tumor adapts to hypoxia first by sustaining itself via anaerobic metabolism and then by stimulating angiogenesis to acquire more nutrients and oxygen. However, the resulting vasculature tends to have aberrant structures with irregular blood flow and leaky walls, paradoxically creating regions of transient hypoxia and reoxygenation (76). Reoxygenation after hypoxia causes DNA damage, exacerbating genomic instability (25). The porous structure of the tumor vasculature may also provide an escape route for metastasizing cells. Repeated cycles of hypoxia, vascular formation, and reoxygenation select for cells that are more likely to survive in a restrictive environment. The consequences of this process are cancer cells that are more aggressive, more likely to metastasize, and more likely to be resistant to radiation and chemotherapy. Intimately tied to this process is the selection for cells that have lost the expression of functional p53 (19).A variety of cellular stresses, including DNA damage, oncogenic transformation, and hypoxia, stabilize the p53 protein by activating a host of stress-inducible kinases that phosphorylate p53 and MDM2, resulting in increased levels of p53 (17). Stabilized ...

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Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites

Cited by 120 publications

References 44 publications

Versatile analysis of multiple macromolecular interactions by SPR imaging: application to p53 and DNA interaction

Versatile analysis of multiple macromolecular interactions by SPR imaging: application to p53 and DNA interaction

WTH3 is a direct target of the p53 protein

Functional Analysis of p53 Binding under Differential Stresses

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