scholarly journals Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas

2020 ◽  
Author(s):  
Huabo Wang ◽  
Jie Lu ◽  
Jordan A. Mandel ◽  
Weiqi Zhang ◽  
Marie Schwalbe ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factor ◽  
Cyst Formation ◽  
Serine Protease Inhibitor ◽  
Metabolic Profiles ◽  
Wide Spread ◽  
Tumor Group ◽  
Electrophilic Stress ◽  
Mutant Forms ◽  
Distinct Features

AbstractBackground and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often bears β-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis.MethodsWe evaluated NFE2L2’s role in HB pathogenesis by co-expressing all combinations of mutant β-catenin, YAPS127A and the patient-derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles and transcriptomes of the ensuing tumors.ResultsIn association with β-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2’s oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth and extracellular matrix. The combination of mutant β-catenin, YAPS127A and Serpin E1, while not accelerating cystogenic tumor growth, did promote the wide-spread necrosis associated with mutant β-catenin-YAPS127A-L30P/R34P tumors.ConclusionsOur findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.

scholarly journals Expression of inter-alpha-trypsin inhibitor heavy chains in endometrium of cyclic and pregnant gilts

Reproduction ◽  
2003 ◽  
pp. 621-627 ◽  
Author(s):  
RD Geisert ◽  
MD Ashworth ◽  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Western Blot ◽  
Protease Inhibitor ◽  
Early Pregnancy ◽  
Trypsin Inhibitor ◽  
Serine Protease Inhibitor ◽  
Oestrous Cycle ◽  
Heavy Chains ◽  
Formation Of Complexes

Attachment of the placenta to the uterus in pigs involves extracellular interaction between the expanding trophoblastic membrane and the thick glycocalyx present on the uterine epithelial microvilli. Formation of complexes between members of inter-alpha-trypsin inhibitor family may function in the maintenance of the extracellular matrix. This study investigated the change in the inter-alpha-trypsin inhibitor heavy chains (ITIH1, ITIH2, ITIH3 and ITIH4) during the oestrous cycle and early pregnancy in pigs. Gene expression of ITIH1, ITIH2, ITIH3 and ITIH4 was detected in the endometrium of cyclic and pregnant gilts; however, gene expression of ITIH was not altered throughout the oestrous cycle or early pregnancy. Western blot analysis with an ITIH antiserum identified the possible linkage forms of ITIH with the serine protease inhibitor, bikunin. Pregnancy altered the release of the various inter-alpha-inhibitor forms from the endometrium during the period of trophoblastic attachment. The results from this study indicate that the inter-alpha-trypsin inhibitor family plays an important role in maintenance of the uterine surface glycocalyx during placental attachment in pigs.

Abstract 311: Osteogenic Transcription Factor Runx2 Represses Connective Tissue Growth Factor Gene Expression And TGFβ Signaling In Vascular Smooth Muscle Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Toru Tanaka ◽  
Takehisa Shimizu ◽  
Norimichi Koitabashi ◽  
Hiroki Matsui ◽  
Hiroshi Doi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Connective Tissue ◽  
Vascular Smooth Muscle Cells ◽  
Tissue Growth ◽  
Matrix Synthesis ◽  
Tgfβ Signaling

[Objective] Runx2, a key transcription factor in osteoblast differentiation, is expressed in calcified atherosclerotic plaques. We have recently shown that Runx2 represses vascular smooth muscle cells (VSMCs) differentiation and promotes their osteogenic differentiation. Connective tissue growth factor (CTGF) has been implicated in the progression to vulnerable plaque by inducing mononuclear cell chemotaxis and VSMCs apoptosis despite of its potent stimulatory effect on connective tissue cell the proliferation and extracellular matrix synthesis. To assess the role of Runx2 in the process of plaque development, we investigated the molecular mechanism of the CTGF gene expression by Runx2 in VSMCs. [Methods and Results] RT-PCR analyses showed that adenovirally overexpressed Runx2 significantly repressed the basal expression of the CTGF gene in human aortic SMCs (HASMCs). Consistent with this, knockdown of the Runx2 expression in HASMCs by small interfering RNA (siRNA) increased CTGF mRNA levels. Luciferase assays showed that Runx2 reduced the transcriptional activity of the CTGF promoter. Transfection of a series of 5′-deletion constructs revealed that Runx2 inhibited CTGF expression through the sequence element located at 5′ untranslated region of CTGF mRNA. We next examined the effects of Runx2 on the TGFβ-induced CTGF expression. Runx2 overexpression significantly repressed CTGF expression in HASMCs stimulated with TGFβ, and knockdown of Runx2 by siRNA enhanced the induction of CTGF expression in response to TGFβ. Runx2 repressed TGFβ-induced CTGF promoter activity through the sequence including Smad binding element (SBE). Overexpression of Runx2 significantly reduced TGFβ- and Smad3-mediated luciferase activity of Smad-dependent promoter which contains four copies of SBE. Biotinylated DNA pulldown assay using SBE of CTGF promoter showed that Runx2 formed a complex with Smad3 and Smad4. [Conclusion] Runx2 repressed basal and TGFβ-induced CTGF gene expression in VSMCs. Thus, in addition to the potential for inducing vascular calcification, Runx2 may affect plaque stability by modulating extracellular matrix synthesis through inhibiting CTGF gene expression and TGFβ signaling.

scholarly journals Pathologic and Radiologic Correlation of Adult Cystic Lung Disease: A Comprehensive Review

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Prajwal Boddu ◽  
Vamsi Parimi ◽  
Michale Taddonio ◽  
Joshua Robert Kane ◽  
Anjana Yeldandi
Keyword(s):  
Cyst Formation ◽  
Diagnostic Challenge ◽  
Diverse Range ◽  
Disease Evolution ◽  
Cystic Lung ◽  
Disease Entities ◽  
The Common ◽  
Review Study ◽  
Distinct Features ◽  
Radiologic Features

The presence of pulmonary parenchymal cysts on computed tomography (CT) imaging presents a significant diagnostic challenge. The diverse range of possible etiologies can usually be differentiated based on the clinical setting and radiologic features. In fact, the advent of high-resolution CT has facilitated making a diagnosis solely on analysis of CT image patterns, thus averting the need for a biopsy. While it is possible to make a fairly specific diagnosis during early stages of disease evolution by its characteristic radiological presentation, distinct features may progress to temporally converge into relatively nonspecific radiologic presentations sometimes necessitating histological examination to make a diagnosis. The aim of this review study is to provide both the pathologist and the radiologist with an overview of the diseases most commonly associated with cystic lung lesions primarily in adults by illustration and description of pathologic and radiologic features of each entity. Brief descriptions and characteristic radiologic features of the various disease entities are included and illustrative examples are provided for the common majority of them. In this article, we also classify pulmonary cystic disease with an emphasis on the pathophysiology behind cyst formation in an attempt to elucidate the characteristics of similar cystic appearances seen in various disease entities.

scholarly journals Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells

2016 ◽  
Vol 36 (24) ◽  
pp. 3100-3112 ◽  
Author(s):  
Tatsuro Iso ◽  
Takafumi Suzuki ◽  
Liam Baird ◽  
Masayuki Yamamoto
Keyword(s):  
Transcription Factor ◽  
Recombinant Protein ◽  
Ubiquitin Ligase ◽  
Stress Responses ◽  
Quantitative Information ◽  
Related Factor ◽  
Electrophilic Stress ◽  
Cullin 3 ◽  
Electrophilic Agent ◽  
Nrf2 Protein

The transcription factor Nrf2 (NF-E2-related-factor 2) is essential for the oxidative and electrophilic stress responses. Keap1 (Kelch-like-ECH-associated-protein 1), an adaptor for a cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and electrophilic stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, and yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during stress responses is unknown. We analyzed the absolute amounts of the Nrf2, Keap1, and Cul3 proteins in five murine cell lines by comparison with serial dilutions of purified recombinant protein standards in combination with quantitative immunoblot analyses. In the basal state, the amount of Nrf2 was maintained at lower levels than those of Keap1 and Cul3 proteins, whereas the electrophilic agent diethylmaleate dramatically increased Nrf2 to a level greater than that of Keap1 and Cul3, resulting in the accumulation of Nrf2 in the nucleus. In contrast, Keap1 and Cul3 did not display any changes in their abundance, subcellular localization, or interaction in response to electrophilic stimuli. Our results demonstrate that the regulation of the Nrf2 protein level during stress responses is mediated by the activity but not the composition of the Nrf2-Keap1-Cul3 complex.

Extracellular matrix modulates insulin production during differentiation of AR42J cells: Functional role of Pax6 transcription factor

2011 ◽  
Vol 112 (1) ◽  
pp. 318-329 ◽  
Author(s):  
Kohei Hamamoto ◽  
Satoko Yamada ◽  
Akemi Hara ◽  
Tsutomu Kodera ◽  
Masaharu Seno ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factor ◽  
Functional Role ◽  
Insulin Production ◽  
Ar42j Cells

scholarly journals EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

2020 ◽  
Vol 21 (5) ◽  
pp. 1664 ◽  
Author(s):  
Emmanuelle Havis ◽  
Delphine Duprez
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factor ◽  
Connective Tissue ◽  
Transcriptional Activity ◽  
Tendon Repair ◽  
Regulatory Elements ◽  
Biological Functions ◽  
Connective Tissues ◽  
Post Translational Modifications ◽  
Matrix Production

Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair.

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