Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway

Abstract Osteonecrosis of the femoral head (ONFH) induced by glucocorticoids (GCs) has been considered to be associated with the dysfunction of bone marrow mesenchymal stem cells (BMSCs). Studies have reported that GCs can regulate the normal differentiation of BMSCs. However, the exact mechanism of this regulation remains unclear. In this study, we used methylprednisolone (MPS) to induce BMSCs, and then found that the Hippo signaling pathway was upregulated in a dose-dependent manner compared to that in the control group. In addition, the osteogenic ability of BMSCs was decreased, as evaluated by Alizarin Red S staining analysis and alkaline phosphatase activity assays, accompanied by the downregulated expression of Runx2, osteopontin, and osteocalcin. Additionally, the adipogenic capacity of BMSCs under the MPS conditions was increased, as identified by Oil Red O staining with upregulated triglyceride and PPARγ expression. Moreover, suppression by knockdown of MST1 was found to attenuate the Hippo signaling pathway and adipogenic differentiation, while enhancing osteogenic differentiation. In conclusion, our findings revealed that the Hippo signaling pathway was involved in GC-ONFH by affecting the osteogenic and adipogenic differentiation capacities of BMSCs. Our study could provide a basis for further investigation of the specific function of the Hippo pathway in ONFH.

Download Full-text

Drosophila Hcf regulates the Hippo signaling pathway via association with the histone H3K4 methyltransferase Trr

Biochemical Journal ◽

10.1042/bcj20180717 ◽

2019 ◽

Vol 476 (4) ◽

pp. 759-768 ◽

Cited By ~ 5

Author(s):

Zi Nan ◽

Weiwei Yang ◽

Jialan Lyu ◽

Fang Wang ◽

Qiannan Deng ◽

...

Keyword(s):

Host Cell ◽

Signaling Pathway ◽

Hippo Pathway ◽

Organ Size ◽

Fundamental Aspect ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Host Cell Factor ◽

Histone H3k4 ◽

The Hippo Pathway

Abstract Control of organ size is a fundamental aspect in biology and plays important roles in development. The Hippo pathway is a conserved signaling cascade that controls tissue and organ size through the regulation of cell proliferation and apoptosis. Here, we report on the roles of Hcf (host cell factor), the Drosophila homolog of Host cell factor 1, in regulating the Hippo signaling pathway. Loss-of-Hcf function causes tissue undergrowth and the down-regulation of Hippo target gene expression. Genetic analysis reveals that Hcf is required for Hippo pathway-mediated overgrowth. Mechanistically, we show that Hcf associates with the histone H3 lysine-4 methyltransferase Trithorax-related (Trr) to maintain H3K4 mono- and trimethylation. Thus, we conclude that Hcf positively regulates Hippo pathway activity through forming a complex with Trr and controlling H3K4 methylation.

Download Full-text

A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa052 ◽

2020 ◽

Vol 26 (9) ◽

pp. 653-664

Author(s):

Challis Karasek ◽

Mohamed Ashry ◽

Chad S Driscoll ◽

Jason G Knott

Keyword(s):

Signaling Pathway ◽

Cell Fate ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Cell Mass ◽

Preimplantation Embryos ◽

Hippo Signaling ◽

Cell Fate Decisions ◽

Hippo Signaling Pathway ◽

The Hippo Pathway

Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

Download Full-text

Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Cancers ◽

10.3390/cancers12092438 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2438 ◽

Cited By ~ 2

Author(s):

Sahar Sarmasti Emami ◽

Derek Zhang ◽

Xiaolong Yang

Keyword(s):

Signaling Pathway ◽

Hippo Pathway ◽

Underlying Mechanism ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Cellular Processes ◽

Wide Range ◽

Future Direction ◽

The Hippo Pathway

The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

Download Full-text

Icariin Protects against Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Rats

Cellular Physiology and Biochemistry ◽

10.1159/000490023 ◽

2018 ◽

Vol 47 (2) ◽

pp. 694-706 ◽

Cited By ~ 16

Author(s):

Zengfa Huang ◽

Cheng Cheng ◽

Beibei Cao ◽

Jing Wang ◽

Hui Wei ◽

...

Keyword(s):

Femoral Head ◽

Osteogenic Differentiation ◽

Bone Repair ◽

Adipogenic Differentiation ◽

Ct Scanning ◽

Control Group ◽

Micro Ct ◽

Alizarin Red ◽

Immunohistochemical Analyses

Background/Aims: Glucocorticoid (GC)-related osteonecrosis of the femoral head (ONFH) is a common complication following administration of steroids to treat many diseases. Our previous study demonstrated that icariin (ICA) might have a beneficial effect on the bone marrow mesenchymal stem cells (BMSCs) of patients with steroid-associated osteonecrosis. In this study, we investigated the underlying mechanisms of ICA associated with the potential enhancement of osteogenesis and anti-adipogenesis in GC-related ONFH. Methods: In vitro cell proliferation was evaluated by CCK-8 assay. Alizarin red S and alkaline phosphatase (ALP) activity were used to measure osteogenic differentiation, while adipogenic differentiation was revealed by oil red O staining and TG content assay. The expression level of osteogenesis-associated genes and PPARγ was evaluated by RT-qPCR, western blotting and immunofluorescence. A total of 30 female SD rats were randomly separated into three groups: a control group, a methylprednisolone (MPS) group and a MPS + ICA group. Serum ALP and TG (triglyceride), micro-CT scanning, histological and immunohistochemical analyses were performed in the animal model. Results: In the in vitro study, ICA promoted proliferation, improved osteogenic differentiation and suppressed adipogenic differentiation of BMSCs treated with MPS. The group treated with MPS and 10-6 M ICA expressed higher levels of Runx2, ALP, bone morphogenetic protein (BMP) 2, and OC and lower expression of PPARγ than the MPS group. In the in vivo study, ICA prevented bone loss in a rat model of GC-related ONFH as shown by micro-CT scanning, histological and immunohistochemical analyses. Conclusions: ICA is an effective compound for promoting bone repair and preventing or delaying the progression of GC-associated ONFH in rats. This effect can be explained by its ability to improve the balance between adipogenesis and osteogenesis, indicating that ICA is an effective candidate for management of GC-associated ONFH.

Download Full-text

Hippo Signaling Pathway Reveals a Spatio-Temporal Correlation with the Size of Primordial Follicle Pool in Mice

Cellular Physiology and Biochemistry ◽

10.1159/000369752 ◽

2015 ◽

Vol 35 (3) ◽

pp. 957-968 ◽

Cited By ~ 25

Author(s):

Cheng Xiang ◽

Jia Li ◽

Liaoliao Hu ◽

Jian Huang ◽

Tao Luo ◽

...

Keyword(s):

Protein Expression ◽

Signaling Pathway ◽

Hippo Pathway ◽

Temporal Correlation ◽

Primordial Follicle ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Primordial Follicle Activation ◽

Spatio Temporal

Background: The Hippo signaling pathway, a highly conserved cell signaling system, exists in most multicellular organisms and regulates cell proliferation, differentiation, and apoptosis. It has been reported that the members of Hippo signaling are expressed in mammalian ovaries, but the exact functions of this pathway in primordial follicle development remains unclear. Methods: To analyze the spatio-temporal correlation between the core component of Hippo pathway and the size of primordial follicle pool, Western blot, Real-time PCR and immunohistochemistry were used, and the expression and localization of MST1, LATS2 and YAP1 mRNA and protein were examined in 3 d, 1 m, 5 m, 16 m postnatal mice ovary and the culture model of mice primordial follicle in vitro. Results: Both the protein and mRNA expression of the MST1 and LATS2 were decreased significantly as mouse age increased (p < 0.05), however, the mRNA expression of them increased significantly in 16 m compared with 5 m as well as the protein expression of LATS2.The expression of YAP showed the opposite trend, and the significant protein expression of pYAP was increased before 1 m, after which no significant change was observed. Moreover, the ratio of pYAP/YAP decreased significantly. Culturing ovaries for 8 d in vitro resulted in the activation of primordial follicles in 3 d postnatal mice ovaries, and these developed into primary follicles with the expression of PCNA increasing significantly (p < 0.05). The mRNA and protein expression of MST and LATS decreased significantly (p < 0.05), and the expression of YAP increased significantly (p < 0.05, p < 0.01), whereas the ratio of pYAP/YAP decreased significantly (p < 0.05). Conclusion: The above results reveal that the expression of the core components of Hippo pathway changed during mouse follicular development, especially before and after primordial follicle activation in vitro. The primordial follicle activation may be related to the significant decrease of the ratio of pYAP1/YAP1. In conclusion, Hippo signaling pathway expressed in mice ovaries and have spatio-temporal correlation with the size of primordial follicle pool.

Download Full-text

WWC Proteins: Important Regulators of Hippo Signaling in Cancer

Cancers ◽

10.3390/cancers13020306 ◽

2021 ◽

Vol 13 (2) ◽

pp. 306

Author(s):

Verena Höffken ◽

Anke Hermann ◽

Hermann Pavenstädt ◽

Joachim Kremerskothen

Keyword(s):

Signaling Pathway ◽

Intracellular Transport ◽

Human Cancer ◽

Hippo Pathway ◽

Tumor Formation ◽

Transport Processes ◽

Published Data ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Upstream Regulators

The Hippo signaling pathway is known to regulate cell differentiation, proliferation and apoptosis. Whereas activation of the Hippo signaling pathway leads to phosphorylation and cytoplasmic retention of the transcriptional coactivator YAP, decreased Hippo signaling results in nuclear import of YAP and subsequent transcription of pro-proliferative genes. Hence, a dynamic and precise regulation of the Hippo signaling pathway is crucial for organ size control and the prevention of tumor formation. The transcriptional activity of YAP is controlled by a growing number of upstream regulators including the family of WWC proteins. WWC1, WWC2 and WWC3 represent cytosolic scaffolding proteins involved in intracellular transport processes and different signal transduction pathways. Earlier in vitro experiments demonstrated that WWC proteins positively regulate the Hippo pathway via the activation of large tumor suppressor kinases 1/2 (LATS1/2) kinases and the subsequent cytoplasmic accumulation of phosphorylated YAP. Later, reduced WWC expression and subsequent high YAP activity were shown to correlate with the progression of human cancer in different organs. Although the function of WWC proteins as upstream regulators of Hippo signaling was confirmed in various studies, their important role as tumor modulators is often overlooked. This review has been designed to provide an update on the published data linking WWC1, WWC2 and WWC3 to cancer, with a focus on Hippo pathway-dependent mechanisms.

Download Full-text

The Hippo Signaling Pathway in Drug Resistance in Cancer

Cancers ◽

10.3390/cancers13020318 ◽

2021 ◽

Vol 13 (2) ◽

pp. 318

Author(s):

Renya Zeng ◽

Jixin Dong

Keyword(s):

Drug Resistance ◽

Cancer Patients ◽

Signaling Pathway ◽

Hippo Pathway ◽

Cancer Drug ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Cancer Drug Resistance ◽

Anti Cancer ◽

Number Of Cycles

Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignancies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of drug resistance. Resistance to drugs administrated to cancer patients greatly limits the benefits that patients can achieve and continues to be a severe clinical difficulty. Among the mechanisms which have been uncovered to mediate anti-cancer drug resistance, the Hippo signaling pathway is gaining increasing attention due to the remarkable oncogenic activities of its components (for example, YAP and TAZ) and their druggable properties. This review will highlight current understanding of how the Hippo signaling pathway regulates anti-cancer drug resistance in tumor cells, and currently available pharmacological interventions targeting the Hippo pathway to eradicate malignant cells and potentially treat cancer patients.

Download Full-text

HPV E6 Protein Associated SOX21-AS1 Promotes YAP/TAZ Activation by Attenuating YAP1 Ubiquitination in Human Cervical Cancer

10.21203/rs.3.rs-55342/v1 ◽

2020 ◽

Author(s):

Qin Liu ◽

Zhiwei Zhu ◽

Senlin Lian ◽

Lixia Zhu ◽

Jiahui Pan ◽

...

Keyword(s):

Cervical Cancer ◽

Signaling Pathway ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Clinical Samples ◽

Hippo Signaling ◽

Dependent Manner ◽

Hpv 16 ◽

Hippo Signaling Pathway ◽

E6 Protein

Abstract Background: The human papillomavirus (HPV), especially HPV 16 type infection, is one of the well-known causes for human cervical cancer, we sought to investigate HPV 16 regulating lncRNA and its role in cervical carcinogenesis. Methods: The potential HPV16 related lncRNAs were screened by using bioinfomatic analysis. The relationship between SOX21-AS1 and clinical features was studied by using clinical samples. Its oncogenic roles were explored in vitro. Results: A HPV 16 infection-specific lncRNA, SOX21-AS1 was spotted by screening the Cancer Genome Atlas TCGA database, and its expression was seriously related to Hippo signaling pathway by using Gene Set Enrichment Analysis. Total 40 cases patients suffered from cervical carcinomas (CCs) were involved, we found that SOX21-AS1 was over-expressed in those CCs patients who were positive for HPV 16 infection compared to those who were negative. We also found that SOX21-AS1 expression was positively related to E6 protein but not E7 expression, which is a carcinogenic protein of HPV 16. Also, YAP1/TAZ/TEAD complex can increase SOX21-AS1 transcription by binding to its promoter region. SOX21-AS1 can promote cell proliferation and invasion in CCs cell lines in a YAP1 activation-dependent manner. We found that SOX21-AS1 can promote YAP1 activation by preventing YAP1 phosphorylation at s127 residue and further preventing its degradation by binding to 14-3-3. Conclusion: In conclusion, SOX21-AS1 is an HPV16 specific lncRNA which can promote tumor growth and metastasis by targeting the Hippo signaling pathway.

Download Full-text

The role of Hippo signaling pathway in physiological cardiac hypertrophy

Bioimpacts ◽

10.34172/bi.2020.32 ◽

2019 ◽

Vol 10 (4) ◽

pp. 251-257

Author(s):

Majid Gholipour ◽

Arezoo Tabrizi

Keyword(s):

Body Weight ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Exercise Group ◽

Expression Level ◽

Control Group ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Physiological Cardiac Hypertrophy

Introduction: The role of Hippo signaling pathway, which was identified by genetic studies as a key regulator for tissue growth and organ size, in promoting physiological cardiac hypertrophy has not been investigated. Methods: Fourteen male Wistar rats were randomly assigned to the exercise and control groups. The exercise group ran 1 hour per day, 5 days/week, at about 65%-75% VO2max on the motor-driven treadmill with 15º slope, and the control group ran 15 min/d, 2 days/week at 9 m/min (0º inclination), throughout the eight-week experimental period. Forty-eight hours after the last session, hearts were dissected and left ventricles were weighed and stored for subsequent RT-PCR analysis. Results: Despite a significant increase in the MAP4k1 expression levels in the exercise group (P = 0.001), the Mst1 expression was inhibited compared to the control group (P < 0.001) which was followed by suppression of Lats1 expression (P = 0.001). Compared with the control group, significant increases were observed in heart weight/body weight (P = 0.024) and left ventricular weight/body weight (P = 0.034) ratios in the exercise group. The H&E staining confirmed the cardiac hypertrophy that may be partly due to a significant increase in Yap1 expression level compared with the control group (P<0.001), which was confirmed by Western blot analysis. Conclusion: Increased MAP4K1 expression did not influence Lats1 activation. The exercise training protocol suppressed Mst1 and Lats1 (Hippo pathway) and caused an increase in Yap1 expression level, which led to physiological cardiac hypertrophy in healthy rats. Further studies are suggested to apply this exercise protocol for the prevention and/or rehabilitation of cardiovascular disease and health promotion.

Download Full-text

Yes-associated protein 1 is required for proliferation and function of bovine granulosa cells in vitro†

Biology of Reproduction ◽

10.1093/biolre/ioz139 ◽

2019 ◽

Vol 101 (5) ◽

pp. 1001-1017 ◽

Cited By ~ 7

Author(s):

Michele R Plewes ◽

Xiaoying Hou ◽

Pan Zhang ◽

Aixin Liang ◽

Guohua Hua ◽

...

Keyword(s):

Signaling Pathway ◽

Nuclear Localization ◽

Granulosa Cells ◽

Hippo Pathway ◽

Critical Role ◽

Small Cells ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

The Hippo Pathway

Abstract Yes-associated protein 1 (YAP1) is a major component of the Hippo signaling pathway. Although the exact extracellular signals that control the Hippo pathway are currently unknown, increasing evidence supports a critical role for the Hippo pathway in embryonic development, regulation of organ size, and carcinogenesis. Granulosa cells (GCs) within the ovarian follicle proliferate and produce steroids and growth factors, which facilitate the growth of follicle and maturation of the oocyte. We hypothesize that YAP1 plays a role in proliferation and estrogen secretion of GCs. In the current study, we examined the expression of the Hippo signaling pathway in bovine ovaries and determined whether it was important for GC proliferation and estrogen production. Mammalian STE20-like protein kinase 1 (MST1) and large tumor suppressor kinase 2 (LATS2) were identified as prominent upstream components of the Hippo pathway expressed in granulosa and theca cells of the follicle and large and small cells of the corpus luteum. Immunohistochemistry revealed that YAP1 was localized to the nucleus of growing follicles. In vitro, nuclear localization of the downstream Hippo signaling effector proteins YAP1 and transcriptional co-activator with PDZ-binding motif (TAZ) was inversely correlated with GC density, with greater nuclear localization under conditions of low cell density. Treatment with verteporfin and siRNA targeting YAP1 or TAZ revealed a critical role for these transcriptional co-activators in GC proliferation. Furthermore, knockdown of YAP1 in GCs inhibited follicle-stimulating hormone (FSH)-induced estradiol biosynthesis. The data indicate that Hippo pathway transcription co-activators YAP1/TAZ play an important role in GC proliferation and estradiol synthesis, two processes necessary for maintaining normal follicle development.

Download Full-text