A Novel p53 Transcriptional Repressor Element (p53TRE) and the Asymmetrical Contribution of Two p53 Binding Sites Modulate the Response of the Placental Transforming Growth Factor-β Promoter to p53

Wong, J. Tze‐Fei; Li, Pei-Xiang; Klamut, Henry J.

doi:10.1074/jbc.m203020200

Cited by 21 publications

(18 citation statements)

References 53 publications

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“…Moreover, neither p53 nor hPitx1 were able to transactivate the PTGFb gene promoter with both the p53-responsive sites mutated, consistent with previous observations that mutation of both sites completely abolished p53 responsiveness. 29 Similar results were obtained for p21, for which hPitx1 was shown to indirectly transactivate the p21 promoter via p53 activation (Figure 8b). …”

supporting

confidence: 72%

“…11 A multitude of p53 target genes have been implicated in this process. 7 Among them, PTGFb 29 and cyclin-dependent kinase inhibitor p21 7,14 are two well-known direct transcriptional targets of p53. To determine whether hPitx1 was able to activate the expression of these two p53 downstream target genes via p53 activation, a luciferase reporter plasmid containing wildtype PTGFb promoter, which possesses two functional p53-responsive elements, was co-transfected into MCF-7 cells with plasmids expressing hPitx1 and its dominant-negative mutant hPitx1-R141P, wild-type p53 and its dominantnegative mutant p53-143A, and/or HPV-E6, the human papilloma virus type-16 E6 oncoprotein that promotes the degradation of p53 through its interaction with the P-labeled probes.…”

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confidence: 99%

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Transcriptional activation of p53 by Pitx1

Lobie

2007

Cell Death Differ

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Little is known about factors that stimulate transcription of the p53 tumor suppressor gene. Here, we report that the human pituitary homeobox 1 (hPitx1) transcription factor increases the expression of p53 at the mRNA and protein levels in human mammary carcinoma (MCF-7) cells. Increased p53 mRNA expression was due to activation of the p53 promoter by hPitx1. hPitx1 bound directly to the p53 promoter and functionally utilized two hPitx1 consensus elements. The predominant consensus element utilized by hPitx1 to stimulate p53 transcription was located within the first exon of the p53 gene. A hPitx1 mutant (hPitx1-R141P) acting as a dominant inhibitor repressed p53 transcription. Forced expression of hPitx1 resulted in cell-cycle arrest and p53-dependent apoptosis in p53-replete MCF-7 cells. Furthermore, hPitx1 stimulated the transcription of p53 target genes involved in cell-cycle arrest and apoptosis (p21 and PTGF-b), again in a p53-dependent manner. Depletion of endogenous hPitx1 by small interfering RNA (siRNA) in MCF-7 cells resulted in decreased basal expression of p53 and consequently of p21 and placental transforming growth factor b (PTGF-b). Depletion of p53 by siRNA dramatically attenuated hPitx1-induced apoptosis in MCF-7 cells. Thus, p53 is a direct transcriptional target gene of hPitx1. This observation is concordant with the recent identification of hPitx1 as a tumor suppressor gene.

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confidence: 72%

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confidence: 99%

Transcriptional activation of p53 by Pitx1

Lobie

2007

Cell Death Differ

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“…9 The promoter of GDF-15 contains two distinct p53-binding sites with different binding affinity to p53 in vitro. Interestingly, Wong et al 51 identified a novel p53 transcriptional repressor element in close proximity of the p53-binding sites, suggesting a complex regulation of activation of GDF-15 in a manner dependent on cell or signaling context. GDF-15 represents a typical gene of the adaptive response to cellular stress, as its expression is generally low in quiescent cells, but is rapidly enhanced by different stress stimuli that employ different signaling pathways.…”

Section: Regulation Of Gdf-15 Expressionmentioning

confidence: 99%

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

Vaňhara

Hampl

Kozubı́k

et al. 2012

Prostate Cancer Prostatic Dis

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Deregulation of expression and function of cytokines belonging to the transforming growth factor-b (TGF-b) family is often associated with various pathologies. For example, this cytokine family has been considered a promising target for cancer therapy. However, the detailed functions of several cytokines from the TGF-b family that could have a role in cancer progression and therapy remain unclear. One of these molecules is growth/differentiation factor-15 (GDF-15), a divergent member of the TGF-b family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with cancer progression, including prostate cancer (PCa). However, studies clearly demonstrating the mechanisms for signal transduction and functions in cell interaction, cancer progression and therapy are still lacking. New GDF-15 roles have recently been identified for modulating osteoclast differentiation and for therapy for PCa bone metastases. Moreover, GDF-15 is as an abundant cytokine in seminal plasma with immunosuppressive properties. We discuss studies that focus on the regulation of GDF-15 expression and its role in tissue homeostasis, repair and the immune response with an emphasis on the role in PCa development.

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“…According to in vitro experiments, the p53 protein binds specifically to a palindromic consensus sequence, RRRCWWGYYY(N 0À13 )RRRCWWGYYY [15], with nearly all REs containing at least one mismatch; in vivo results have suggested that the spacer region may be much smaller [14,15]. The sequence is typically located within 5,000 bases of the target gene's transcriptional start site, and p53 either induces or represses expression upon p53 binding [16,17]. One feature of p53 that confounds the discovery of novel transregulated genes is that while some binding sites match the expected consensus sequence quite well, others can be consensus poor and yet are both necessary, and sufficient, to transactivate a gene [18].…”

Section: Introductionmentioning

confidence: 99%

Divergent Evolution of Human p53 Binding Sites: Cell Cycle Versus Apoptosis

Horvath¹,

Wang²,

Resnick³

et al. 2005

PLoS Genet

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The p53 tumor suppressor is a sequence-specific pleiotropic transcription factor that coordinates cellular responses to DNA damage and stress, initiating cell-cycle arrest or triggering apoptosis. Although the human p53 binding site sequence (or response element [RE]) is well characterized, some genes have consensus-poor REs that are nevertheless both necessary and sufficient for transactivation by p53. Identification of new functional gene regulatory elements under these conditions is problematic, and evolutionary conservation is often employed. We evaluated the comparative genomics approach for assessing evolutionary conservation of putative binding sites by examining conservation of 83 experimentally validated human p53 REs against mouse, rat, rabbit, and dog genomes and detected pronounced conservation differences among p53 REs and p53-regulated pathways. Bona fide NRF2 (nuclear factor [erythroid-derived 2]-like 2 nuclear factor) and NFjB (nuclear factor of kappa light chain gene enhancer in B cells) binding sites, which direct oxidative stress and innate immunity responses, were used as controls, and both exhibited high interspecific conservation. Surprisingly, the average p53 RE was not significantly more conserved than background genomic sequence, and p53 REs in apoptosis genes as a group showed very little conservation. The common bioinformatics practice of filtering RE predictions by 80% rodent sequence identity would not only give a false positive rate of ;19%, but miss up to 57% of true p53 REs. Examination of interspecific DNA base substitutions as a function of position in the p53 consensus sequence reveals an unexpected excess of diversity in apoptosis-regulating REs versus cell-cycle controlling REs (rodent comparisons: p , 1.0 eÀ12). While some p53 REs show relatively high levels of conservation, REs in many genes such as BAX, FAS, PCNA, CASP6, SIVA1, and P53AIP1 show little if any homology to rodent sequences. This difference suggests that among mammalian species, evolutionary conservation differs among p53 REs, with some having ancient ancestry and others of more recent origin. Overall our results reveal divergent evolutionary pressure among the binding targets of p53 and emphasize that comparative genomics methods must be used judiciously and tailored to the evolutionary history of the targeted functional regulatory regions.Citation: Horvath MM, Wang X, Resnick MA, Bell DA (2007) Divergent evolution of human p53 binding sites: Cell cycle versus apoptosis. PLoS Genet 3(7): e127.

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A Novel p53 Transcriptional Repressor Element (p53TRE) and the Asymmetrical Contribution of Two p53 Binding Sites Modulate the Response of the Placental Transforming Growth Factor-β Promoter to p53

Cited by 21 publications

References 53 publications

Transcriptional activation of p53 by Pitx1

Transcriptional activation of p53 by Pitx1

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

Divergent Evolution of Human p53 Binding Sites: Cell Cycle Versus Apoptosis

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