Regulation of the Human Plasminogen Activator Inhibitor Type 2 Gene

Stringer, Brett W.; Udofa, Ekemini A.; Antalis, Toni M.

doi:10.1074/jbc.m111.318758

Cited by 13 publications

(5 citation statements)

References 46 publications

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“…For example, the TGAGTCA motif identified in genes in Cluster 19 is a known binding site for activator protein-1 (AP-1), which is a family of dimeric basic region-leucine zipper (bZIP) proteins that includes the Jun and Fos sub-families ( 45 , 46 ). A repressive role of the AP-1 binding site in serpinb2 transcription has been recently identified ( 47 ). Consistently, this motif is carried by 87% (6/7) of the genes involved in the ‘negative regulation of endopeptidase activity’ (Figure 4B ), including five serpins in zebrafish.…”

Section: Resultsmentioning

confidence: 99%

Global identification of the genetic networks andcis-regulatory elements of the cold response in zebrafish

Liu

Zhang

et al. 2015

Nucleic Acids Res

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The transcriptional programs of ectothermic teleosts are directly influenced by water temperature. However, the cis- and trans-factors governing cold responses are not well characterized. We profiled transcriptional changes in eight zebrafish tissues exposed to mildly and severely cold temperatures using RNA-Seq. A total of 1943 differentially expressed genes (DEGs) were identified, from which 34 clusters representing distinct tissue and temperature response expression patterns were derived using the k-means fuzzy clustering algorithm. The promoter regions of the clustered DEGs that demonstrated strong co-regulation were analysed for enriched cis-regulatory elements with a motif discovery program, DREME. Seventeen motifs, ten known and seven novel, were identified, which covered 23% of the DEGs. Two motifs predicted to be the binding sites for the transcription factors Bcl6 and Jun, respectively, were chosen for experimental verification, and they demonstrated the expected cold-induced and cold-repressed patterns of gene regulation. Protein interaction modeling of the network components followed by experimental validation suggested that Jun physically interacts with Bcl6 and might be a hub factor that orchestrates the cold response in zebrafish. Thus, the methodology used and the regulatory networks uncovered in this study provide a foundation for exploring the mechanisms of cold adaptation in teleosts.

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Section: Resultsmentioning

confidence: 99%

Global identification of the genetic networks andcis-regulatory elements of the cold response in zebrafish

Liu

Zhang

et al. 2015

Nucleic Acids Res

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“…The c-Jun, c-Fos and FosB which are SerpinB2 transcription factors [28] increased in MDA-MB-231 miR-200c/141 cells compared to control. miR-124a and miR-26b which are able to target SepinB2 [29] decreased in MDA-MB-231 miR-200c/141 cells compared to control.…”

Section: Discussionmentioning

confidence: 99%

microRNA-200c/141 upregulates SerpinB2 to promote breast cancer cell metastasis and reduce patient survival

et al. 2017

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The microRNA-200 (miR-200) family is associated with tumor metastasis and poor patient prognosis. We found that miR-200c/141 cluster overexpression upregulated SerpinB2 in the MDA-MB-231 triple-negative (TN) breast cancer cell line. We observed transcription factor (c-Jun, c-Fos, and FosB) upregulation, nuclear localization of c-Jun, and increased SerpinB2 promoter-directed chloramphenicol acetyltransferase activity in miR-200c/141 cluster-overexpressing cells relative to controls. Additionally, miR-124a and miR-26b, which directly target SepinB2, were downregulated compared to controls. In mouse xenograft models, miR-200c/141 cluster overexpression promoted lymph node and lung metastasis, and siRNA-mediated SerpinB2 knockdown decreased lung metastasis, suggesting that SerpinB2 mediates miR-200c/141-induced lung metastasis. We also explored the clinical significance of SerpinB2 protein status through analysis of primary breast tumor samples and The Cancer Genome Atlas (TCGA) data. High SerpinB2 levels were associated with reduced survival and increased lymph node metastasis in breast cancer patients. SerpinB2 was overexpressed in the TN breast cancer subtype as compared to the luminal subtype. The present study demonstrates that SerpinB2 promotes miR-200c/141 cluster overexpression-induced breast cancer cell metastasis, and SerpinB2 overexpression correlates with increased metastatic potential and unfavorable outcomes in breast cancer patients. SerpinB2 may be a useful biomarker for assessing metastasis risk in breast cancer patients.

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“…Particularly, PAI-1 is critically involved in the tight balance of pro- and anticoagulation and has been considered an acute-phase protein [3]. A variety of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin (IL)-1, and IL-6 as well as growth factors, hormones, and vasoactive peptides have been shown to stimulate PAI-1 production [4–7]. The inflammatory response after cerebral ischemia promotes fibrin clot formation by induction of PAI-1 and reduction of tPA plasma levels in stroke patients compared to controls [8].…”

Section: Introductionmentioning

confidence: 99%

PAI-1 but Not PAI-2 Gene Deficiency Attenuates Ischemic Brain Injury After Experimental Stroke

Griemert

Pelz

Engelhard

et al. 2018

Transl. Stroke Res.

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After stroke, secondary brain damage is influenced by the extent of fibrin clot formation. This is counteracted by the endogenous fibrinolysis. Of major interest are the key players of the fibrinolytic plasminogen activator system including the urokinase plasminogen activator (uPA), the tissue-type plasminogen activator (tPA), and their endogenous inhibitors plasminogen activator inhibitor 1 (PAI-1) and PAI-2. The role of PAI-1 in brain injury is well established, whereas the importance of PAI-2 is unknown at present. The objectives of the present were twofold: first, to characterize the time-dependent cerebral mRNA expression of the plasminogen activator system (PAS) after brain ischemia and second, to investigate the impact of PAI-1 and PAI-2 on brain infarct volume using gene-deficient mice. Adult C57Bl/6J mice were subjected to unilateral transient middle cerebral artery occlusion (MCAO) followed by reperfusion for 3, 24, 72, or 120 h. Quantitative PCR revealed that brain mRNA expression levels of the PAS components, and particularly of PAI-1 (237-fold) and PAI-2 (19-fold), peaked at 24 h after stroke. Accordingly, PAI-1 plasma activity was strongly increased. Brain infarct volume in TTC (2,3,5-triphenyltetrazolium chloride)-stained brain sections was significantly smaller 24 h after MCAO in PAI-1-deficient mice (- 31%), but not in PAI-2-deficient mice (- 6%). Thus, endogenous upregulation of PAI-1, but not of PAI-2, might contribute to increased brain damage after acute ischemic stroke. The present study therefore shows that PAI-2 is induced by brain ischemia, but does not play an important or relevant role for secondary brain damage after brain injury.

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Regulation of the Human Plasminogen Activator Inhibitor Type 2 Gene

Cited by 13 publications

References 46 publications

Global identification of the genetic networks andcis-regulatory elements of the cold response in zebrafish

Global identification of the genetic networks andcis-regulatory elements of the cold response in zebrafish

microRNA-200c/141 upregulates SerpinB2 to promote breast cancer cell metastasis and reduce patient survival

PAI-1 but Not PAI-2 Gene Deficiency Attenuates Ischemic Brain Injury After Experimental Stroke

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