scholarly journals Photoperiod-induced differential expression of angiogenesis genes in testes of adult Peromyscus leucopus

Reproduction ◽  
2005 ◽  
Vol 129 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Leah M Pyter ◽  
Andrew K Hotchkiss ◽  
Randy J Nelson
Keyword(s):  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Peromyscus Leucopus ◽  
Hypoxia Inducible Factor ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Day Length ◽  
Plasminogen Activator Inhibitor 1 ◽  
Short Day ◽  
Short Days

Non-pathological angiogenesis in adults is rare and is largely thought to be restricted to wound healing and female reproductive cycles. Adult male rodents, however, display seasonal angiogenesis to support seasonal changes in reproductive tissue morphology. Non-tropical rodents use photoperiod (day length) to determine the time of year. During short days, the reproductive system undergoes involution and mating behaviours stop, adaptations which presumably allow energy resources to be shifted to processes necessary for winter survival. We compared the patterns of gene expression involved in angiogenesis in testes of white-footed mice (Peromyscus leucopus) following 7, 14, 21 or 34 weeks of long or short day lengths. Short days decreased body mass, reproductive tract mass and seminiferous tubule diameter. Potential genes involved in seasonal angiogenesis were screened by hybridizing testicular RNA from each group to angiogenesis-specific microarrays. Genes that were ≥6-fold different between long- and short-day testes (i.e. hypoxia-inducible factor 1α(Hif1α), plasminogen activator inhibitor 1 (Serpine1), transforming growth factor β receptor 3 (Tgfβr3) and tumour necrosis factor (Tnf)) were sequenced and expression differences were compared throughout gonadal regression and recrudescence using quantitative RT-PCR. Our results suggest that short days trigger expression ofHif1α,Serpine1, andTgfβr3to inhibit angiogenesis or promote apoptosis during testicular regression, and also trigger expression ofTnfto promote angiogenesis during testicular recrudescence.

Differential Mechanisms of Plasminogen Activator Inhibitor-1 Gene Activation by Transforming Growth Factor-β and Tumor Necrosis Factor-α in Endothelial Cells

2001 ◽  
Vol 86 (12) ◽  
pp. 1563-1572 ◽  
Author(s):  
Yan Chen ◽  
Joanne Sloan-Lancaster ◽  
David Berg ◽  
Mark Richardson ◽  
Brian Grinnell ◽  
...  
Keyword(s):  
Map Kinases ◽  
Transforming Growth Factor ◽  
Gene Activation ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Promoter Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Factor Α ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (SERPIN) specific for tissue-type and urokinase-like plasminogen activators. High plasma PAI-1 activity is a risk factor for thrombotic diseases. Due to the short half-life of PAI-1, regulation of PAI-1 gene expression and secretion of active PAI-1 into the blood stream is important for hemostatic balance. We have investigated transcriptional control of PAI-1 gene expression in bovine aortic endothelial cells (BAECs) and human cell lines using PAI-1 5’ promoter-luciferase reporter assays. Contrary to the cytokine-induced up-regulation of PAI-1 mRNA and protein levels, we found that only transforming growth factor-β (TGF-β) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-α (TNF-α) induced a small luciferase activity with the 2.5 kb PAI-1 promoter, but not with the PAI-800/4G/5G and p3TP-lux promoters. Next we investigated whether a lack of response to TNF-α was due to deficient signaling pathways. BAECs responded to TNF-α with robust NFκB promoter activation. TGF-β activated the p38 MAP kinase, while TNF-α activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-α stimulation with activation of the MAP kinases and the NFκB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-β and TNF-α and found no difference. PAI-1 gene activation by TNF-α apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-β is the most important cytokine for PAI-1 transcriptional activation through its 5’ proximal promoter.

scholarly journals Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 399 ◽  
Author(s):  
David Radke ◽  
Qi Ling ◽  
Robert Häsler ◽  
Gökhan Alp ◽  
Hendrik Ungefroren ◽  
...  
Keyword(s):  
Transient Expression ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma ◽  
Type Ii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pancreatic Cancer Cells ◽  
Micro Rnas

The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play important roles in PDAC biology by acting as either tumour suppressors through induction of cell death or tumour promoters through induction of pro-inflammatory signalling, invasion and metastasis. TRAIL-R2 can also associate with nuclear proteins and alter the maturation of micro RNAs (miRs). By genome-wide miR profiling and quantitative PCR analyses we now demonstrate that knockdown of TRAIL-R1 in PDAC cells decreased the level of mature miR-370 and led to an increased abundance of the type II receptor for transforming growth factor β (TGFβ). Transfection of cells with an artificial miR-370-3p decreased the levels of TGFβ-RII. We further show that transient expression of the miR-370 mimic decreased TGFβ1-induced expression of SERPINE1 encoding plasminogen activator-inhibitor 1 and partially relieved TGFβ1-induced growth inhibition. Moreover, stable TRAIL-R1 knockdown in Colo357 cells increased TGFβ1-induced SERPINE1 expression and this effect was partially reversed by transient expression of the miR-370 mimic. Finally, after transient knockdown of TRAIL-R1 in Panc1 cells there was a tendency towards enhanced activation of Smad2 and JNK1/2 signalling by exogenous TGFβ1. Taken together, our study reveals that TRAIL-R1 through regulation of miR-370 can decrease the sensitivity of PDAC cells to TGFβ and therefore represents a potential tumour suppressor in late-stage PDAC.

Case Studies Discussing the Pathology, Immunogenicity, and Proposed Mechanism of Toxicity of an Inhaled Anti-TGFβ Humanized Fab Antibody in Non-Human Primates and Mice

2020 ◽  
pp. 019262332096002
Author(s):  
Anthony Peter Hall ◽  
Annick Cauvin ◽  
Sherri Dudal ◽  
James Raymond ◽  
Petrina Rogerson ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Inflammatory Cell ◽  
Transforming Growth Factor ◽  
Systemic Exposure ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Lavage Fluid ◽  
T Cell Response ◽  
Plasminogen Activator Inhibitor 1 ◽  
Draining Lymph Nodes

Treatment of nonhuman primates and mice with a humanized antigen-binding fragment (Fab) antibody (UCBFab) inhibiting transforming growth factor β via daily inhalation for up to 13 weeks resulted in low systemic exposure but high local exposure in the lung. Target engagement was demonstrated by reduced levels of signal transducers, phosphoSMAD and plasminogen activator inhibitor-1 in the bronchoalveolar lavage fluid (BALF). Treatment was associated with a high frequency and titer of antidrug antibodies, indicating high local immunogenicity, and local pathology within the lung and draining lymph nodes. Microscopic changes were characterized by perivascular (PV) and peribronchiolar (PB) mononuclear inflammatory cell (MIC) infiltrates that were principally lymphocytic in nature and mixed inflammatory cell infiltrates and/or inflammation within the alveoli. Immunohistochemical investigation revealed a predominantly CD68-positive macrophage and CD3- and CD8>CD4-positive T-cell response in the alveoli, whereas within the airways, there was a variable mixture of CD3-positive T cells, CD20-positive B cells, and CD68-positive macrophages. Increased cellularity of the draining lymph nodes was also noted, indicating the presence of an immune response to the inhaled test article. Morphologic changes did not progress over time, and all changes partially recovered. Increased leukocytes (principally macrophages) in BALF cytology correlated with the changes seen by histopathology.

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