Targeting the TGFβ signalling pathway in disease

Akhurst, Rosemary J.; Hata, Akiko

doi:10.1038/nrd3810

Cited by 1,297 publications

(1,231 citation statements)

References 231 publications

(253 reference statements)

Supporting

Mentioning

1,208

Contrasting

Unclassified

Order By: Relevance

“…TGF‐βs can exert their actions through activation of the canonical (Smad‐dependent), and/or noncanonical signaling pathways (Akhurst & Hata, 2012). We have addressed the question whether activation of the canonical pathway is linked to the observed 4AP‐ and TGF‐β‐dependent increase of NBCe1 protein (Figure 1d).…”

Section: Resultsmentioning

confidence: 99%

“…TGF‐β has been shown to regulate several transport proteins in astrocytes (Rathore, Redensek, & David, 2012). TGF‐βs exert their effects in a cell‐ and context‐dependent manner through several signaling pathways (Akhurst & Hata, 2012). In the present study, TGF‐β regulates NBCe1 through at least two signaling pathways: the canonical, Smad‐dependent, and the JNK pathway (Figures 3 and 4).…”

Section: Discussionmentioning

confidence: 99%

“…Binding of ligand to the receptor complex leads to the phosphorylation of the type II receptor kinase and activation of type I receptor kinase that leads to the propagation of signaling. The canonical, Smad‐mediated, TGF‐β signaling pathway implies phosphorylation of Smad2 and Smad3 proteins, formation of a complex with Smad4, and translocation into the nucleus, where transcription of target genes is activated (Derynck & Miyazono, 2008; Miyazawa, Shinozaki, Hara, Furuya, & Miyazono, 2002; Moustakas & Heldin, 2009, reviewed in Akhurst & Hata, 2012). However, TGF‐β may also signal through other signaling pathways, such as ERK, p38, JNK, and MAPK pathways (Yang et al, 2003) that may act independently or in co‐operation with the canonical pathway.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Khakipoor

Ophoven

Schrödl-Häußel

et al. 2017

Glia

View full text Add to dashboard Cite

The electrogenic sodium bicarbonate cotransporter NBCe1 (SLC4A4) expressed in astrocytes regulates intracellular and extracellular pH. Here, we introduce transforming growth factor beta (TGF‐β) as a novel regulator of NBCe1 transcription and functional expression. Using hippocampal slices and primary hippocampal and cortical astrocyte cultures, we investigated regulation of NBCe1 and elucidated the underlying signaling pathways by RT‐PCR, immunoblotting, immunofluorescence, intracellular H(+) recording using the H(+) ‐sensitive dye 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein, mink lung epithelial cell (MLEC) assay, and chromatin immunoprecipitation. Activation of TGF‐β signaling significantly upregulated transcript, protein, and surface expression of NBCe1. These effects were TGF‐β receptor‐mediated and suppressed following inhibition of JNK and Smad signaling. Moreover, 4‐aminopyridine (4AP)‐dependent NBCe1 regulation requires TGF‐β. TGF‐β increased the rate and amplitude of intracellular H+ changes upon challenging NBCe1 in wild‐type astrocytes but not in cortical astrocytes from Slc4a4‐deficient mice. A Smad4 binding sequence was identified in the NBCe1 promoter and Smad4 binding increased after activation of TGF‐β signaling. The data show for the first time that NBCe1 is a direct target of TGF‐β/Smad4 signaling. Through activation of the canonical pathway TGF‐β acts directly on NBCe1 by binding of Smad4 to the NBCe1 promoter and regulating its transcription, followed by increased protein expression and transport activity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Khakipoor

Ophoven

Schrödl-Häußel

et al. 2017

Glia

View full text Add to dashboard Cite

show abstract

“…26e29 In support of this latter view, recombinant TGF-b3 (Avotermin) showed no antiscarring effect in clinical trials. 30 Because P311 stimulates up-regulation of all three TGFbs, we sought to determine whether P311 might play a functional role in fibrogenesis, focusing on cutaneous scar formation as a model. Scarring is the end point of adult cutaneous wound healing, which can be divided into the following three phases: inflammatory, proliferative, and remodeling.…”

mentioning

confidence: 99%

Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

Cheng

Yue

Aslam

et al. 2017

The American Journal of Pathology

View full text Add to dashboard Cite

Neuronal protein 3.1 (P311), a conserved RNA-binding protein, represents the first documented protein known to stimulate transforming growth factor (TGF)-b1 to -b3 translation in vitro and in vivo. Because TGF-bs play critical roles in fibrogenesis, we initiated efforts to define the role of P311 in skin scar formation. Here, we show that P311 is up-regulated in skin wounds and in normal and hypertrophic scars. Genetic ablation of p311 resulted in a significant decrease in skin scar collagen deposition. Lentiviral transfer of P311 corrected the deficits, whereas down-regulation of P311 levels by lentiviral RNA interference reproduced the deficits seen in P311 À/À mice. The decrease in collagen deposition resulted in scars with reduced stiffness but also reduced scar tensile strength. In vitro studies using murine and human dermal fibroblasts showed that P311 stimulated TGF-b1 to -b3 translation, a process that involved eukaryotic translation initiation factor 3 subunit b as a P311 binding partner. This resulted in increased TGF-b levels/activity and increased collagen production. In addition, P311 induced dermal fibroblast activation and proliferation. Finally, exogenous TGF-b1 to -b3, each restituted the normal scar phenotype. These studies demonstrate that P311 is required for the production of normal cutaneous scars and place P311 immediately up-stream of TGF-bs in the process of fibrogenesis. Conditions that decrease P311 levels could result in less tensile scars, which could potentially lead to higher incidence of dehiscence after surgery. (Am J Pathol 2017, 187: 292e303; http://dx

show abstract

“…The oncogenic response to TGFβ has prompted the design of therapies based on the blockade of the TGFβ signal ( 6,7 ). Several inhibitors of the TGFβ pathway are being developed in clinical trials, and some patients are benefi tting from anti-TGFβ-based therapies ( 8,9 ).…”

Section: Introductionmentioning

confidence: 99%

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

Rodón¹,

Gonzàlez-Juncà²,

Inda³

et al. 2014

Cancer Discovery

View full text Add to dashboard Cite

In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identifi ed cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. SIGNIFICANCE:TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. Cancer Discov; 4(10); 1230-41.

show abstract

Targeting the TGFβ signalling pathway in disease

Cited by 1,297 publications

References 231 publications

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

Contact Info

Product

Resources

About