Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53

Resnick‐Silverman, Lois; Clair, Selvon St.; Maurer, Matthew; Zhao, Kathy; Manfredi, James J.

doi:10.1101/gad.12.14.2102

Cited by 109 publications

(94 citation statements)

References 29 publications

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“…It is well demonstrated that p53 has different affinities for distinct p53REs, which would allow the p53 transcriptional program to be modulated by the nuclear concentration of p53 (Resnick-Silverman et al, 1998;Szak et al, 2001). At low concentrations of p53, only target genes carrying high affinity p53REs would be regulated.…”

Section: Keyword: Affinitymentioning

confidence: 99%

Mechanisms of regulatory diversity within the p53 transcriptional network

2008

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Section: Keyword: Affinitymentioning

confidence: 99%

Mechanisms of regulatory diversity within the p53 transcriptional network

2008

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“…Additional reporter constructs used included: 1.5 kb TRAIL-promoter-Luc [22], 1 kb cFLIP-promoter-Luc [23,24] and p53RE-Luc [25]. Transient transfection of different reporter constructs (1 μg) together with pCMV-βgal (0.25μg) into 5×10 5 melanoma cells was performed using Lipofectamine (Life Technologies-Invitrogen).…”

Section: Transfection and Luciferase Assaymentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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“…8,9 Sequence-specific binding of wild-type p53 to p53 response elements (p53REs) within the DNA is essential for its role as a tumor suppressor. The transactivation of different target genes differs: 10 some genes require high p53 levels, which are induced only upon exposure to p53-activating stress, whereas others are already upregulated by endogenous p53 levels. Most proapoptotic signaling pathways, including those induced by DNA damage, growth factor depletion and cytosolic calcium overload, converge on the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Regulation of AIF expression by p53

et al. 2006

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The tumor suppressor p53 plays a pivotal role in suppressing tumorigenesis by inducing genomic stability, cell cycle arrest or apoptosis. AIF is a mitochondrial protein, which, upon translocation to the nucleus, can participate in apoptosis, primarily in a caspase-independent contexts. We now report that AIF gene expression is subject to positive transcriptional regulation by p53. Interestingly, unlike most known p53 target genes, the AIF gene is regulated by basal levels of p53, and activation of p53 by genotoxic stress does not result in a substantial further increase in AIF expression. The AIF gene harbors a p53 responsive element, which is bound by p53 within cells. p53 drives efficient induction of large-scale DNA fragmentation, a hallmark of AIF activity. Importantly, caspase-independent death is compromised in cells lacking functional p53, in line with the known role of AIF in this process. Thus, in addition to its documented effects on caspase-dependent apoptosis, p53 may also sensitize cells to caspase-independent death through positive regulation of AIF expression. Moreover, in the absence of overt apoptotic signals, the constitutive induction of AIF by p53 may underpin a cytoprotective maintenance role, based on the role of AIF in ensuring proper mitochondrial function.

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Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53

Cited by 109 publications

References 29 publications

Mechanisms of regulatory diversity within the p53 transcriptional network

Mechanisms of regulatory diversity within the p53 transcriptional network

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Regulation of AIF expression by p53

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