Epidermal growth factor regulates PAI-1 expression via activation of the transcription factor Elk-1

Wyrzykowska, Paulina; Stalińska, Krystyna; Wawro, Mateusz; Kochan, Jakub; Kasza, Aneta

doi:10.1016/j.bbagrm.2010.08.004

Cited by 18 publications

(13 citation statements)

References 17 publications

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“…As mentioned in section 2.5, PAI-1 promoter (pm) 1 contained TATA box, c-Ets, Elk-1, NFkB, and C/EBP; pm2 contained p300 and USF-2; pm3 contained C/EBP and AP-1; and pm4 contained c-Ets, NRF-2 binding site. It has been reported that EGF activates Ets binding site by phosphorylation of Elk1 (49); hypoxia activates C/EBP (24); oxidative stress activates AP-1 (47); EGF receptor activation activates NF-B, steroid receptor coactivator-1 potentiates TGF-␤/Smad signal, facilitating the functional link between Smad3 and p300/CBP (8); and TGF-␤ signal facilitates Smad/p53/USF-2 transcriptional complex (40), resulting in PAI-1 transcription (39). In addition, shRNA knock-down of Nrf2 and loss of Nrf2/Smad3/Smad4 complex resulted in increased transcription of PAI-1.…”

Section: Discussionmentioning

confidence: 99%

“…We designed the ChIP PCR primers for four randomly segmented regions, which contained the transcription factor binding sites reported by others (24,40,47,49), or oxidative stress or inflammation-related transcription factor binding sites predicted by us. ChIP PCR primer sequences were 5=-AGGCTCGAG-GAAGGGAATTCCAAA-3= and 5=-TGATCCAGCTGTGCTC-CGTT-3= for Ϫ289 to approximately ϩ45 of the PAI-1 promoter (pm) region (PAI-1 pm1) when the TATA site was set as 0; 5=-ACACCAGGAGAGTCTGGCCCATGT-3= and 5=-ACTTCAAGTC-CTTTCCTCCTCCCT-3= for Ϫ596 to approximately Ϫ507 of PAI-1 pm (PAI-1 pm2); 5-=AGCTGCAGATTGAGTTCCAGGCTA-3= and 5=-TTTGTGTCAATAGCCCTTGTGCGG-3= for Ϫ895 to approximately Ϫ611 of PAI-1 pm (PAI-1 pm3); and 5=-AACTTCCATTCCCAACAC-CCACGA-3= and 5=-TTCTGCCTCCTGAGTGCTCGATTA-3= for Ϫ1,130 to approximately Ϫ930 of PAI-1 pm (PAI-1 pm4) sense and antisense, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury

Kim

Jung

Park

2013

American Journal of Physiology-Renal Physiology

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Male gender and the male hormone testosterone increase susceptibility to kidney ischemia and reperfusion (I/R) injury, which is associated with inflammatory responses. Possible involvement of histone deacetylase (HDAC) in inflammatory responses has been suggested. We investigated the gender-specific role of HDACs in plasminogen activator inhibitor type-1 (PAI-1) expression and I/R injury. PAI-1 inhibition protected the kidney from I/R-induced inflammation and functional loss. Among HDACs, only HDAC11 negatively regulated PAI-1 expression in I/R-subjected kidney gender specifically and lipopolysaccharide (LPS)-stimulated mouse monocytes/macrophages. HDAC11 gene silencing increased PAI-1 expression. Chromatin immunoprecipitation assay confirmed binding of HDAC11 to the promoter region of PAI-1 and then release by I/R insult or LPS treatment. I/R-induced HDAC11 release was inhibited by orchiectomy and reversed by dihydrotestosterone treatment. Release of HDAC11 increased acetylation of histone H3. In conclusion, male gender and male hormones accelerate I/R-induced decreases in expression and binding of HDAC11, resulting in an increase in PAI-1 expression. These data provide important insight into gender dimorphism offering HDAC11 as a novel target for I/R injury.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury

Kim

Jung

Park

2013

American Journal of Physiology-Renal Physiology

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“…These data indicate that PAI‐1 may be upstream of EGF and EGF receptor signaling. EGF‐treated breast adenocarcinoma and glioma cells rapidly up‐regulate PAI‐1 expression (32, 33). TGF‐β–induced PAI‐1 expression requires EGF receptor–mediated signaling (34).…”

Section: Discussionmentioning

confidence: 99%

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

et al. 2017

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Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; ) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as and In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1 mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.

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“…Elk-1 belongs to the ternary complex factor subfamily, which is a subgroup of the Ets family of transcription factors. 35, 36 Elk-1 participates in the regulation of many important genes, such as c-fos, 37 plasminogen activator inhibitor-1, 38 EZH2, 39 Mcl-1, 40 PKC alpha 41 and cyclin D1, 42 which are involved in the regulation of cell proliferation and apoptosis. Elk-1 is associated with tumorigenesis of many different malignant diseases, such as cancer of the breast, 42, 43 colon, 44 endometrium 45 and HCC.…”

Section: Discussionmentioning

confidence: 99%

Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A

Hung

Chen

et al. 2014

Cell Death Dis

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Protein phosphatase 2A (PP2A) is a tumor suppressor, which is functionally defective in various cancers. Previously, we found that PP2A activity determined the anticancer effect of bortezomib and erlotinib in hepatocellular carcinoma (HCC) cells. Here, we tested a novel erlotinib derivative, TD52, in four HCC cell lines, PLC5, Huh-7, Hep3B and Sk-Hep1. Using MTT and flow cytometry, we showed that TD52 had more potent apoptotic effects than erlotinib in HCC cells. TD52-induced apoptosis was associated with dose- and time- dependent reactivation of PP2A and downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A) and p-Akt. Inhibition of PP2A or ectopic expression of CIP2A or Akt in PLC5 cells abolished the effects of TD52. Furthermore, we demonstrated that TD52 affected the binding of Elk-1 to the proximal promoter of the CIP2A gene, thus downregulating transcription of CIP2A. Importantly, TD52-induced tumor inhibition was associated with reactivation of PP2A and downregulation of CIP2A and p-Akt in vivo. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A determines the apoptotic effect induced by TD52. Our findings disclose the therapeutic mechanism of this novel targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

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Epidermal growth factor regulates PAI-1 expression via activation of the transcription factor Elk-1

Cited by 18 publications

References 17 publications

Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury

Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury

Plasminogen activator inhibitor‐1 regulates macrophage‐dependent postoperative adhesion by enhancing EGF‐HER1 signaling in mice

Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A

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