15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Transcriptional Activity of Estrogen Receptor-α via Covalent Modification of DNA-Binding Domain

Kim, Han-Jong; Kim, Joon‐Young; Meng, Zhaojing; Wang, Li Hua; Liu, Fa; Conrads, Thomas P.; Burke, Terrence R.; Veenstra, Timothy D.; Farrar, William L.

doi:10.1158/0008-5472.can-06-3043

Cited by 46 publications

(52 citation statements)

References 41 publications

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“…For instance, 15d-PGJ 2 inhibited NF-B signaling through binding to IB kinase and NF-B (67,68), and also inhibited AP-1 activity by interaction with c-Jun (69). In addition to inflammation-associated transcription factors, there are reports that 15d-PGJ 2 also regulates the activities of several proteins, including H-Ras and estrogen receptor-␣ (70,71). Based on these reports and our current findings, it is possible that such PGs may functionally associate with certain signaling molecules in the TLR2-specific signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Regulation of TLR2 Expression by Prostaglandins in Brain Glia

Yoon

Jeon

Kim

et al. 2008

The Journal of Immunology

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TLR have emerged as important primary sensors for diverse stimuli and are increasingly implicated in various diseases. However, the molecular mechanisms underlying the regulation of the TLR system remain poorly understood. In this study, we report that some PGs may control TLR-mediated inflammatory events through modulation of TLR2 expression in brain immune cells. We first found that 15-deoxy-Δ12,14-PG J2 (15d-PGJ2) markedly altered the expression of TLR2 but not TLR4, TLR1, and TLR9 at the message and protein levels in activated glia. Down-regulation of TLR2 expression and downstream events of TLR2 activation, including phagocytosis by 15d-PGJ2, were also observed in cells treated with representative TLR2 ligands such as lipoteichoic acid and Pam3CSK4. We further revealed that certain 15d-PGJ2-related PGs such as 15d-PGD2 and PGD2 also suppressed the ligand-stimulated increase of TLR2 expression, whereas PGE2 and arachidonic acids did not. Interestingly, TLR2 expression was down-regulated even when such PGs were added at several hours after stimulator treatment. These findings appear to be independent of peroxisome proliferator-activated receptor γ and D prostanoid receptors (DPs) because potent synthetic peroxisome proliferator-activated receptor γ agonists, selective DP1 agonist, or DP2 agonist did not mimic the effects of such PGs on TLR2 expression. Taken together, our results suggest that 15d-PGJ2, 15d-PGD2, and PGD2 may play notable roles as modulators of the TLR2-mediated inflammatory events, and provide new insight into the resolution of inflammation in the brain.

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Section: Discussionmentioning

confidence: 99%

Regulation of TLR2 Expression by Prostaglandins in Brain Glia

Yoon

Jeon

Kim

et al. 2008

The Journal of Immunology

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“…All cells were cultured as previously described [14][15][16][17]. VCaP cells were a generous gift from Ken Pienta, University of Michigan.…”

Section: Cell Culturementioning

confidence: 99%

Co-expression of the toleragenic glycoprotein, CD200, with markers for cancer stem cells

Kawasaki

Mistree

Hurt

et al. 2007

Biochemical and Biophysical Research Communications

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Tumor immunology fundamentals suggest immunological surveillance has the ability to recognize malignant cells and kill them before a tumor develops. However, cancer cells employ evasion mechanisms whereby the immune system may be actively suppressed or even tolerized to the tumor. Recently cancer stem cells were linked to tumor initiation and formation. However, no reports have addressed whether these cells participate in a tumor's ability to evade immune surveillance. Recently the glycoprotein CD200, expressed within the innate immune system and other tissues and cells, was shown to be involved in tolerance. Here we describe CD200 co-expression with stem cell markers found on prostate, breast, brain, and colon cancers. This is the first report describing an immunomodulatory molecule on epithelial cancer stem cells. This important finding suggests a mechanism by which a tumor might evades immune system detection.

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“…Because of the a,bunsaturated carbonyl group that constitutes the electrophilic carbon center, cyPGs are prone to undergo Michael addition reactions with various nucleophiles (Noyori and Suzuki, 1993), such as the free sulfhydryl group of cysteine residues located in reduced glutathione (Cagen et al, 1975;Atsmon et al, 1990;Parker and Ankel, 1992;Gayarre et al, 2005) or many redoxregulated cellular proteins (Rossi et al, 2000;Straus et al, 2000;Cernuda-Morollon et al, 2001;Oliva et al, 2003;Perez-Sala et al, 2003;Shibata et al, 2003). Of particular interest is 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), one of the terminal products of the COX-2-mediated arachidonic acid pathway, that has been shown to covalently modify several transcription factors and other signaling molecules, including nuclear factorkB (Rossi et al, 2000;Straus et al, 2000;CernudaMorollon et al, 2001), H-Ras (Oliva et al, 2003), thioredoxin (Shibata et al, 2003), AP-1 (Perez-Sala et al, 2003), Keap1 (Levonen et al, 2004;Oh et al, 2008), peroxisome proliferator-activated receptor-g (Shiraki et al, 2005), eukaryotic initiation factor 4F (Kim et al, 2007b) and estrogen receptor-a (Kim et al, 2007a).…”

Section: Introductionmentioning

confidence: 99%

15-Deoxy-Δ12,14-prostaglandin J2 stabilizes, but functionally inactivates p53 by binding to the cysteine 277 residue

Kim

et al. 2010

Oncogene

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15-Deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), a representative cyclopentenone prostaglandin, has many interesting biological effects. In this study, treatment of human breast cancer cells (MCF-7) with 15d-PGJ 2 led to accumulation of p53 protein. However, the p53 DNA binding and its transcriptional activity were significantly reduced. 15d-PGJ 2 directly modified p53 as verified by reacting recombinant p53 with biotinylated 15d-PGJ 2 . 9,10-Dihydro-15-deoxy-D 12,14 -prostaglandin J 2 lacking the electrophilic a,b-unsaturated functionality failed to inhibit p53 DNA binding as well as to modify p53. Moreover, by conducting an in vitro [ 35 S]-labeled p53 translation assay, we identified cysteine 277 as a putative site of p53 modification by 15d-PGJ 2 . The DNA-binding ability of a mutant p53 in which cysteine 277 was substituted by alanine was virtually unaffected by 15d-PGJ 2 . Likewise, p53 binding activity of biotinylated 15d-PGJ 2 was abolished in mutant cells. In addition, cells expressing wild-type p53 exhibited p53 protein stability to a greater extent than mutant C277A cells. In conclusion, 15d-PGJ 2 can undergo nucleophilic addition to p53, presumably at the cysteine 277 residue, rendering this tumor suppressor less susceptible to proteasomal degradation.

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15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Transcriptional Activity of Estrogen Receptor-α via Covalent Modification of DNA-Binding Domain

Cited by 46 publications

References 41 publications

Regulation of TLR2 Expression by Prostaglandins in Brain Glia

Regulation of TLR2 Expression by Prostaglandins in Brain Glia

Co-expression of the toleragenic glycoprotein, CD200, with markers for cancer stem cells

15-Deoxy-Δ12,14-prostaglandin J2 stabilizes, but functionally inactivates p53 by binding to the cysteine 277 residue

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