scholarly journals Strigolactone regulates shoot development through a core signalling pathway

2016 ◽  
Author(s):  
Tom Bennett ◽  
Yueyang Liang ◽  
Madeleine Seale ◽  
Sally Ward ◽  
Dörte Müller ◽  
...  

ABSTRACTStrigolactones are a recently identified class of hormone that regulate multiple aspects of plant development. The DWARF14 (D14) α/β fold protein has been identified as a strigolactone receptor, which can act through the SCFMAX2 ubiquitin ligase, but the universality of this mechanism is not clear. Multiple proteins have been suggested as targets for strigolactone signalling, including both direct proteolytic targets of SCFMAX2, and downstream targets. However, the relevance and importance of these proteins to strigolactone signalling in many cases has not been fully established. Here we assess the contribution of these targets to strigolactone signalling in adult shoot developmental responses. We find that all examined strigolactone responses are regulated by SCFMAX2 and D14, and not by other D14-like proteins. We further show that all examined strigolactone responses likely depend on degradation of SMXL proteins in the SMXL6 clade, and not on other proposed proteolytic targets. Taken together, our results suggest that in the adult shoot, the dominant mode of strigolactone signalling is D14-initiated, MAX2-mediated degradation of SMXL6-related proteins. We confirm that the BRANCHED1 transcription factor and the PIN-FORMED1 auxin efflux carrier are plausible downstream targets of this pathway in the regulation of shoot branching, and show that BRC1 likely acts in parallel to PIN1.AUTHOR SUMMARYStrigolactones are a recently discovered family plant hormones with diverse roles in development, most strikingly in the regulation shoot branching. Our understanding of the mechanism(s) by which plants perceive and respond to strigolactones is growing rapidly. It is likely that the strigolactone signaling pathway has evolved by duplication and diversification of specific components of a pre-existing pathway, involved in perception and response to an as yet unknown hormone. Several of these components have been identified and several new candidate components have been implicated in the pathway. We have adopted a genetic approach to assess systematically the contributions of all these players to strigolactone signaling in the shoot. We exclude some of the candidate proteins from involvement in strigolactone-mediated shoot branching control and define a core pathway for strigolactone action in the shoot. We provide evidence that downstream of this core, the strigolactone signaling pathway branches, with different effectors mediating different shoot responses.

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haoqi Zhao ◽  
Lan Wang ◽  
Shufang Wang ◽  
Xihua Chen ◽  
Min Liang ◽  
...  

Abstract Background Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial–mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified. Methods The expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting. Results CHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002. Conclusion These results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.


2021 ◽  
Author(s):  
Stephanie C. Kerr ◽  
Suyash Patil ◽  
Alexandre de Saint Germain ◽  
Jean‐Paul Pillot ◽  
Julie Saffar ◽  
...  

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 821
Author(s):  
Wanglong Qiu ◽  
Chia-Yu Kuo ◽  
Yu Tian ◽  
Gloria H. Su

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.


2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Garima Sharma ◽  
Ashish Ranjan Sharma ◽  
Eun-Min Seo ◽  
Ju-Suk Nam

The Wnt signaling pathway is mediated by a family of secreted glycoproteins through canonical and noncanonical mechanism. The signaling pathways are regulated by various modulators, which are classified into two classes on the basis of their interaction with either Wnt or its receptors. Secreted frizzled-related proteins (sFRPs) are the member of class that binds to Wnt protein and antagonizes Wnt signaling pathway. The other class consists of Dickkopf (DKK) proteins family that binds to Wnt receptor complex. The present review discusses the disease related association of various polymorphisms in Wnt signaling modulators. Furthermore, this review also highlights that some of the sFRPs and DKKs are unable to act as an antagonist for Wnt signaling pathway and thus their function needs to be explored more extensively.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Iris Appelmann ◽  
Azam Salimi ◽  
Michael Huber ◽  
Mirle Schemionek ◽  
Margherita Vieri ◽  
...  

Background Activating RAS mutations drive around 30% of pre-B cell acute lymphoblastic leukemias (pre-B ALL) and are particularly common in relapsed ALL with a consecutively poor outcome. Recently published data demonstrated the critical role of the unfolded protein response (UPR) network, namely its IRE1α-XBP1 axis, for the survival of pre-B ALL cells: High expression of XBP1 confers a poor prognosis in pre B-ALL. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre-B ALL. In this study, we aimed at identifying the molecular mechanism underlying pro-survival IRE1α-XBP1 signaling in RAS mutated pre-B ALL. Methods For a TET-ON inducible NRASG12D model in conditional Xbp1 knockout mice, we used interleukin 7 (IL-7)-dependent murine Mx1-Cre;Xbp1fl/fl pre-B cells transduced with a TET-ON inducible NRASG12D. We performed in vitro cell cycle and apoptosis assays with propidium iodide (PI) and annexin-V/PI. Furthermore, Western Blot and RT-qPCR were applied to analyze target gene expression. In a second approach, we focused on the signaling events following the blockade of RAS downstream targets using the MEK inhibitor PD0325901 and the dual PI3K/mTOR inhibitor BEZ235. We then assessed the efficacy of small molecule inhibition of IRE1α by MKC-8866 on XBP1 inactivation in RAS-mutated pre-B ALL cells either as a single treatment and in combination with the above mentioned drugs. Results We found the expression of Xbp1 significantly increased at the mRNA level with induction of NRASG12D. To determine the significance of Xbp1 in NRASG12D-driven pre-B ALL, we genetically deleted the IRE1α target Xbp1 using Cre-mediated deletion of Xbp1fl/fl in our mouse model of pre-B ALL. Genetic loss of Xbp1 significantly induced apoptosis (2.0-fold, p<0.0001) and caused cell cycle arrest (induction of G0/1, 1.7-fold, p=0.0003) along with an increase in the expression of CDK inhibitors, p21CIP1 and p27KIP1 at the protein level. Genetic ablation of Xbp1 abrogated IL-7 receptor (IL-7R) signaling by reducing the phosphorylation levels of STAT5-Y694 and JAK1-Y1022/Y1023. In an additional approach, we revealed that IL-7-deprived pre-B ALL cells reduce the mRNA expression of Xbp1s, indicating that Xbp1 acts as a downstream linchpin of the IL-7 receptor signaling pathway. Both IL-7-deprivation and genetic loss of Xbp1 increased the phosphorylation levels of ERK1/2-T202/Y204, AKT-S473 and the protein levels of NRASG12D and MAPK negative regulator DUSP6. Pharmacological inhibition of XBP1 activation using MKC-8866 resulted in similar effects on the expression of RAS downstream targets. We therefore tested MKC-8866 in combination with MEK inhibition by PD0325901 as a potential therapeutic strategy against pre-B ALL, which proved non-efficient. As a second option with therapeutic implications, we focused on the PI3K pathway which acts downstream of both the IL-7R and RAS signaling pathways. Strikingly, we observed that genetic ablation of Xbp1 (viable cells after 72 h, BEZ: 71.9 ± 9.0 vs BEZ+ Mx1-Cre;Xbp1fl/f: 10.0 ± 4.9) or pharmacological inhibition of its production with MKC-8866 (viable cells after five days, BEZ: 58.0 ± 6.8 vs BEZ+ MKC-8866: 13.3 ± 7.4) sensitizes pre-B ALL to dual inhibition of PI3K/mTOR with BEZ235. By applying the Bliss formula, we were able to show that BEZ235 in combination with MKC-8866 synergistically reduces the viability of RAS-mutated pre-B ALL cells. Gene expression analysis indicated that BEZ235 in combination with MKC-8866 fully blocked IL-7R signaling and caused an aberrant activation of Ras-Erk signaling. Targeting PI3K/mTOR signaling along with XBP1 inactivation increased expression of NRASG12D and its target DUSP6. In addition, we showed that combined therapy increased expression levels of p19Arf in RAS-mutated pre-B ALL, implicating cell senescence mediated by activated RAS signaling. Conclusion Our work strongly supports the hypothesis that XBP1 induces its positive effects on progression of pre-B ALL cells through the IL-7R signaling pathway. IL-7R signaling through its downstream effector XBP1 counteracts the RAS signaling pathway to promote leukemogenesis in pre-B ALL cells. Active XBP1 prevents the cytotoxic effects of BEZ235 in pre-B ALL cells, and hence targeting XBP1 in combination with dual PI3K/mTOR inhibition by BEZ235 appears as a promising targeted strategy against the "undruggable" driver RAS in NRASG12D-mutated pre-B ALL. Disclosures Brümmendorf: Janssen: Consultancy; Merck: Consultancy; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding.


Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1881
Author(s):  
Dongyeop Jang ◽  
Hayeong Jeong ◽  
Chang-Eop Kim ◽  
Jungtae Leem

Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on obesity through network pharmacological approaches. We revealed that targets of AMGB are significantly associated with obesity-related and adipocyte-elevated genes. Evodiamine, berberine, genipin, palmitic acid, genistein, and quercetin were shown to regulate adipocytokine signaling pathway proteins which mainly involved tumor necrosis factor receptor 1, leptin receptor. In terms of the regulatory pathway of lipolysis in adipocytes, norephedrine, pseudoephedrine, quercetin, and limonin were shown to affect adrenergic receptor-beta, protein kinase A, etc. We also found that AMGB has the potentials to enhance the insulin signaling pathway thereby preventing type II diabetes mellitus. Additionally, AMGB was discovered to be able to control not only insulin-related proteins but also inflammatory mediators and apoptotic regulators and caspases, hence reducing hepatocyte injury in nonalcoholic fatty liver disease. Our findings help develop a better understanding of how AMGB controls obesity.


2021 ◽  
Author(s):  
Xiu Mei Ma ◽  
Kang Geng ◽  
Betty Yuen-Kwan Law ◽  
Peng Wang ◽  
Yue Li Pu ◽  
...  

Abstract Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissue. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was resulted from PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.


2020 ◽  
Vol 48 (06) ◽  
pp. 1369-1383
Author(s):  
Shi-Ye Ke ◽  
Ding-Hui Liu ◽  
Lin Wu ◽  
Xian-Guan Yu ◽  
Min Wang ◽  
...  

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.


2020 ◽  
Vol 48 (8) ◽  
pp. 030006052094616 ◽  
Author(s):  
Xiaofei Li ◽  
Ruifang Tian ◽  
Lan Liu ◽  
Lihui Wang ◽  
Dong He ◽  
...  

Objective Radiotherapy plays an important role in the treatment of colorectal cancer (CRC). However, some patients benefit minimally from radiotherapy because of radioresistance. This study investigated the effects of andrographolide on radiosensitivity in HCT116 CRC cells and examined its mechanism of action. Methods Cell survival, proliferation, apoptosis, and migration were evaluated using MTT, colony formation, flow cytometry, and Transwell cell invasion assays, respectively. Glycolysis-related indicators were measured to examine cell glycolytic activity. The expression of related proteins was detected by western blotting. Results After andrographolide treatment, the expression of phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway-related proteins, glycolytic activity, and cell survival and invasion rates were decreased in HCT116 cells. Andrographolide plus irradiation increased apoptosis and decreased survival, invasion, and colony formation compared with the effects of irradiation alone. Conclusion Andrographolide enhanced radiosensitivity by downregulating glycolysis via inhibition of the PI3K-Akt-mTOR signaling pathway in HCT116 cells.


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