Identification of PARP-1 as one of the transcription factors binding to the repressor element in the promoter region of COX-2

Lin, Yan; Tang, Xinyi; Zhu, Yunxia; Shu, Tingting; Han, Xiao

doi:10.1016/j.abb.2010.09.016

Cited by 22 publications

(12 citation statements)

References 27 publications

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“…Indeed, mutation of the E-box region of the Ptgs2 promoter, which is adjacent to one of the ATF/CRE sites (i.e., CRE-1), increases Ptgs2 expression in response to LPS, indicating that an endogenous repressor acts as a negative regulator of Ptgs2 transcription [36]. Moreover, other factors, such as PARP-1, have been shown to repress Ptgs2 transcription by binding to previously unrecognized repression elements in the Ptgs2 promoter far upstream of the transcription start site (−655/−632) [7]. Our results strengthen the view that transcriptional repression of Ptgs2 is an important regulatory mechanism controlling the expression of Ptgs2 during acute inflammation by demonstrating that Atf3 is rapidly recruited to the Ptgs2 promoter and negatively regulates Ptgs2 expression.…”

Section: Discussionmentioning

confidence: 99%

Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation

Hellmann

Tang

Zhang

et al. 2015

Prostaglandins & Other Lipid Mediators

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By generating prostaglandins, cyclooxygenase-2 (Cox-2/Ptgs2) plays a critical role in regulating inflammatory responses. While several inflammatory stimuli have been shown to increase Ptgs2 expression, less is known about how the transcription of this gene is terminated. Here we show that stimulation of macrophages with yeast zymosan, a TLR2/6 and dectin-1 agonist, causes a transient increase in the expression of Ptgs2 accompanied by a simultaneous increase in the expression of the transcriptional repressor, Activating transcription factor-3 (Atf3). The expression of Ptgs2 was significantly higher in resident peritoneal macrophages isolated from Atf3−/− mice than that from Atf3+/+ mice and was associated with higher prostaglandin production upon stimulation with zymosan. In activated macrophages, Atf3 accumulated in the nucleus and chromatin-immunoprecipitation analysis showed that Atf3 is recruited to the Ptgs2 promoter region. In acute peritonitis and in cutaneous wounds, there was increased leukocyte accumulation and higher levels of prostaglandins (PGE2/PGD2) in inflammatory exudates of Atf3−/− mice compared with WT mice. Collectively, these results demonstrate that during acute inflammation Atf3 negatively regulates Ptgs2 and therefore dysregulation of this axis could potentially contribute to aberrant Ptgs2 expression in chronic inflammatory diseases. Moreover, this axis could be a new therapeutic target for suppressing Ptgs2 expression and the resultant inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation

Hellmann

Tang

Zhang

et al. 2015

Prostaglandins & Other Lipid Mediators

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“…Increased AP-2 expression suppresses cancer cell growth (102) and may inhibit ras oncogene-mediated transformation (101), effects likely diminished by PARP inhibition (Figure 1). PARP-1 has also been shown to bind the inhibitory element of COX-2, which mediates inflammation and promotes VEGF-mediated pro-angiogenesis pathways activated in cancer cells (103, 104). …”

Section: Gene Transcriptionmentioning

confidence: 99%

Beyond DNA Repair: Additional Functions of PARP-1 in Cancer

2013

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Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent nuclear enzymes that transfer negatively charged ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD+) to a variety of protein substrates, altering protein–protein and protein-DNA interactions. The most studied of these enzymes is poly(ADP-ribose) polymerase-1 (PARP-1), which is an excellent therapeutic target in cancer due to its pivotal role in the DNA damage response. Clinical studies have shown susceptibility to PARP inhibitors in DNA repair defective cancers with only mild adverse side effects. Interestingly, additional studies are emerging which demonstrate a role for this therapy in DNA repair proficient tumors through a variety of mechanisms. In this review, we will discuss additional functions of PARP-1 – including regulation of inflammatory mediators, cellular energetics and death pathways, gene transcription, sex hormone- and ERK-mediated signaling, and mitosis – and the role these PARP-1-mediated processes play in oncogenesis, cancer progression, and the development of therapeutic resistance. As PARP-1 can act in both a pro- and anti-tumor manner depending on the context, it is important to consider the global effects of this protein in determining when, and how, to best use PARP inhibitors in anticancer therapy.

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“…Cyclooxygenase-2 (COX-2) is also involved in generating free radicals and has been shown to be regulated by NFjB. In the case of COX-2, however, a more direct regulatory link may be more important: PARP-1 has been demonstrated to bind to the mouse COX-2 promoter region through interactions with the inhibitory element resulting in the inhibition of COX-2 expression [49].…”

Section: Inflammatory Mediators: Inos Cox-2 and Mmpsmentioning

confidence: 99%

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

Bai

Virág

2012

FEBS Letters

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a b s t r a c t PARP enzymes influence the immune system at several key points and thus modulate inflammatory diseases. PARP enzymes affect immune cell maturation and differentiation and regulate the expression of inflammatory mediators such as cytokines, chemokines, inducible nitric oxide synthase and adhesion molecules. Moreover, PARP enzymes are key regulators of cell death during inflammationrelated oxidative and nitrosative stress. Here we provide an overview of the different inflammatory diseases regulated by PARP enzymes.

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Identification of PARP-1 as one of the transcription factors binding to the repressor element in the promoter region of COX-2

Cited by 22 publications

References 27 publications

Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation

Atf3 negatively regulates Ptgs2/Cox2 expression during acute inflammation

Beyond DNA Repair: Additional Functions of PARP-1 in Cancer

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

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