scholarly journals Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters

2019 ◽  
Vol 20 (9) ◽  
pp. 2347 ◽  
Author(s):  
Thomas Kietzmann
Keyword(s):  
Transcription Factors ◽  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Cell Types ◽  
Whole Body ◽  
Liver Zonation ◽  
Current Review ◽  
Health And Disease ◽  
The Hippo Pathway ◽  
Dynamic Interplay

The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis.

scholarly journals Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 611
Author(s):  
Kelly Coffey
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cellular Localisation ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
Emergence Of Resistance

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

scholarly journals A83 INTESTINAL EPITHELIAL CELL STEMNESS AND DIFFERENTIATION ARE REGULATED BY THE HIPPO PATHWAY EFFECTOR YAP1

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 97-98
Author(s):  
S Fallah ◽  
J Beaulieu
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Hippo Pathway ◽  
High Rate ◽  
Intestinal Cell ◽  
Intestinal Differentiation ◽  
Ht29 Cells ◽  
The Hippo Pathway

Abstract Background The high rate of cell turnover in the intestinal epithelium is supported by the LGR5+ crypt base columnar (CBC) stem cells, which are located at the lower part of the gland. Among of the various factors and signals like Wnt and Notch, YAP1 (yes associated protein) also plays an important role in stemness of CBC stem cells. YAP1 is the effector of the Hippo pathway. Hippo Pathway restricts the cells proliferation, tissues overgrowth and cancer formation through the phosphorylation and inactivation of the YAP1 protein. When active, YAP1 transfers into nucleus, forms the complex with TEADs transcription factors and promotes the transcription of genes involved in cell growth and proliferation. Aims In the present study, we investigated the role of the YAP1 in the colorectal cancer multipotent HT29 cell line, which contain cancer stem cells (CSC). Methods For approaching to this goal, YAP1 expression was knocked down using shRNAs in HT29 cells. Then stem cells and intestinal cell lineages (secretory goblet, Paneth and enteroendocrine and absorptive) markers expression was analyzed using qPCR and Western blot. Results The results showed the reduction of the expression of stem cells markers including LGR5 in YAP1 knockdown HT29 cells compare with control. Expression of the goblet cells markers (MUC2 and trefoil factor 3) and absorptive cells markers (sucrase-isomaltase and dipeptidylpeptidase IV) were significantly increased in YAP1 knockdown cells but Paneth (DEFA5 and lysozyme) and enteroendocrine (CHGA) were not detected. Finally, examination of the main transcription factors for intestinal differentiation revealed an increase in CDX2 expression. Conclusions These results suggest that YAP1 is involved in the maintenance of colorectal cancer stem cells while preventing intestinal differentiation in both secretory and absorptive lineages through the repression of CDX2. Funding Agencies CIHR

scholarly journals The Hippo pathway coactivator Yorkie can reprogram cell fates and create compartment-boundary–like interactions at clone margins

2020 ◽  
Vol 6 (50) ◽  
pp. eabe8159
Author(s):  
Joanna C. D. Bairzin ◽  
Maya Emmons-Bell ◽  
Iswar K. Hariharan
Keyword(s):  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Activity Levels ◽  
Cell Fates ◽  
Cubitus Interruptus ◽  
Compartment Boundary ◽  
Pathway Activation ◽  
Chromatin Regulator ◽  
Heterotypic Interactions ◽  
The Hippo Pathway

During development, tissue-specific patterns of gene expression are established by transcription factors and then stably maintained via epigenetic mechanisms. Cancer cells often express genes that are inappropriate for that tissue or developmental stage. Here, we show that high activity levels of Yki, the Hippo pathway coactivator that causes overgrowth in Drosophila imaginal discs, can also disrupt cell fates by altering expression of selector genes like engrailed (en) and Ultrabithorax (Ubx). Posterior clones expressing activated Yki can down-regulate en and express an anterior selector gene, cubitus interruptus (ci). The microRNA bantam and the chromatin regulator Taranis both function downstream of Yki in promoting ci expression. The boundary between Yki-expressing posterior clones and surrounding wild-type cells acquires properties reminiscent of the anteroposterior compartment boundary; Hedgehog signaling pathway activation results in production of Dpp. Thus, at least in principle, heterotypic interactions between Yki-expressing cells and their neighbors could activate boundary-specific signaling mechanisms.

scholarly journals Activation of the Hippo Pathway in Rana sylvatica: Yapping Stops in Response to Anoxia

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1422
Author(s):  
Aakriti Gupta ◽  
Kenneth B. Storey
Keyword(s):  
Dna Binding ◽  
Gene Transcription ◽  
Hippo Pathway ◽  
Rana Sylvatica ◽  
Whole Body ◽  
Nuclear Fraction ◽  
Wood Frogs ◽  
Downstream Targets ◽  
Protein Levels ◽  
The Hippo Pathway

Wood frogs (Rana sylvatica) display well-developed anoxia tolerance as one component of their capacity to endure prolonged whole-body freezing during the winter months. Under anoxic conditions, multiple cellular responses are triggered to efficiently cope with stress by suppressing gene transcription and promoting activation of mechanisms that support cell survival. Activation of the Hippo signaling pathway initiates a cascade of protein kinase reactions that end with phosphorylation of YAP protein. Multiple pathway components of the Hippo pathway were analyzed via immunoblotting, qPCR or DNA-binding ELISAs to assess the effects of 24 h anoxia and 4 h aerobic recovery, compared with controls, on liver and heart metabolism of wood frogs. Immunoblot results showed significant increases in the relative levels of multiple proteins of the Hippo pathway representing an overall activation of the pathway in both organs under anoxia stress. Upregulation of transcript levels further confirmed this. A decrease in YAP and TEAD protein levels in the nuclear fraction also indicated reduced translocation of these proteins. Decreased DNA-binding activity of TEAD at the promoter region also suggested repression of gene transcription of its downstream targets such as SOX2 and OCT4. Furthermore, changes in the protein levels of two downstream targets of TEAD, OCT4 and SOX2, established regulated transcriptional activity and could possibly be associated with the activation of the Hippo pathway. Increased levels of TAZ in anoxic hearts also suggested its involvement in the repair mechanism for damage caused to cardiac muscles during anoxia. In summary, this study provides the first insights into the role of the Hippo pathway in maintaining cellular homeostasis in response to anoxia in amphibians.

scholarly journals Localized JNK signaling regulates organ size during development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Helen Rankin Willsey ◽  
Xiaoyan Zheng ◽  
José Carlos Pastor-Pareja ◽  
A Jeremy Willsey ◽  
Philip A Beachy ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Size Control ◽  
Organ Size ◽  
Control Mechanisms ◽  
Cancer Therapies ◽  
Independent Manner ◽  
Jnk Signaling ◽  
New Strategy ◽  
The Hippo Pathway

A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.

209 Rho signaling-directed regulation of YAP/TAZ in parthenogenetic stem cells

2020 ◽  
Vol 32 (2) ◽  
pp. 233
Author(s):  
G. Pennarossa ◽  
S. Arcuri ◽  
F. Gandolfi ◽  
T. Brevini
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Hippo Pathway ◽  
Genetic Material ◽  
Embryonic Stem ◽  
Cell Types ◽  
Embryonic Cell ◽  
And Migration ◽  
The Hippo Pathway

Mammalian oocyte maturation is characterised by asymmetric meiotic division that is regulated by specific cytoskeleton organisation. Similarly, during early embryonic divisions, one of the most important steps is the establishment of polarity that allows cells to adopt distinct developmental fates. All of these events are driven by dynamic changes in actin filaments. It has been demonstrated recently that the Rho signalling pathway plays a key role in the organisation and rearrangement of actin-containing structures, regulating cell polarity and migration. In addition, beside its effect on cell cytoskeleton, Rho directly interacts with the Hippo pathway, influencing both embryonic cell proliferation and differentiation. Because both Rho and Hippo are expressed by the oocyte and maternally inherited (Zhang et al. 2014 Cell Cycle 13, 3390-3403, https://doi.org/10.4161/15384101.2014.952967; Menchero et al. 2017 Dev. Dyn. 246, 245-261, https://doi.org/10.1002/dvdy.24471), we investigated their regulation in parthenogenetic embryonic stem cells (ParthESC) that possess exclusively maternal genetic material, and compared the results with biparental ESCs. Previous results obtained by whole-transcriptome analysis revealed the presence of several differentially expressed genes involved in the Rho pathway and showed no differences for most of the Hippo signalling genes. To better elucidate the molecular mechanisms involved, in the present study, we dissected the expression pattern of the Rho and Hippo regulatory genes in human biparental ESCs and ParthESC. Experiments were performed on 4 biparental ESC and 4 ParthESC lines using cells between passages 5 to 25. The results showed significantly increased transcription of the Rho GTPase family genes (RHOA, RHOB, and RHOC) in ParthESC compared with biparental ESCs. Consistent with this, 12 of 17 Rho activators were significantly upregulated, whereas 8 of 11 Rho inhibitors were significantly decreased in ParthESC. Furthermore, monoparental cells displayed significantly higher expression levels of YAP and TAZ, whereas the upstream genes involved in the Hippo pathway (LATS1/2, MOB1, MST1/2, NF2) were comparable in the two cell types. Interestingly, a significantly higher total YAP protein content was detected in ParthESC, whereas the quantity of the phosphorylated form was comparable in the two cell types. This accounts for the observed upregulation of Rho genes, which stimulate the assembly of contractile actin stress fibres, inhibiting LATS1/2 phosphorylation and preventing subsequent phosphorylation of YAP/TAZ (Yu and Guan 2013 Genes Dev. 27, 355-371; https://doi.org/10.1101/gad.210773.112). Altogether, our results suggest that the Rho pathway may regulate YAP/TAZ behaviour via a LATS/MST/NF2-independent process in ParthESC, similarly to a previous report in oocytes (Posfai and Rossant 2016 Cell Res. 26, 393-394; https://doi.org/10.1038/cr.2016). Although further clarifications are needed, we hypothesise that the regulatory mechanisms detected in ParthESC may be related to their strictly maternal origin, with a possible impact on their plasticity and potency. This study was supported by Carraresi Foundation. Authors are members of the COST Actions CA16119.

scholarly journals Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Cancers ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 81 ◽  
Author(s):  
◽  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Therapeutic Potential ◽  
Hippo Pathway ◽  
Large Body ◽  
Hippo Signaling ◽  
Wide Range ◽  
The Hippo Pathway

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

scholarly journals Angiocrine signaling in the hepatic sinusoids in health and disease

2016 ◽  
Vol 311 (2) ◽  
pp. G246-G251 ◽  
Author(s):  
Enis Kostallari ◽  
Vijay H. Shah
Keyword(s):  
Endothelial Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Cell Types ◽  
Hepatocyte Proliferation ◽  
Liver Sinusoidal Endothelial Cells ◽  
Functional Changes ◽  
Liver Zonation ◽  
Health And Disease ◽  
Short Synthesis

The capillary network irrigating the liver is important not only for nutrient and oxygen delivery, but also for the signals distributed to other hepatic cell types necessary to maintain liver homeostasis. During development, endothelial cells are a key component in liver zonation. In adulthood, they maintain hepatic stellate cells and hepatocytes in quiescence. Their importance in pathobiology is highlighted in liver regeneration and chronic liver diseases, where they coordinate paracrine cell behavior. During regeneration, liver sinusoidal endothelial cells induce hepatocyte proliferation and angiogenesis. During fibrogenesis, they undergo morphological and functional changes, which are reflected by their role in hepatic stellate cell activation, inflammation, and distorted sinusoidal structure. Therapeutic strategies to target angiocrine signaling are in progress but are in the early stages. Here, we offer a short synthesis of recent studies on angiocrine signaling in liver homeostasis, regeneration, and fibrogenesis.

scholarly journals A new perspective on the evolution of the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors

2020 ◽  
Author(s):  
Yannick Mesrouze ◽  
Gustavo Aguilar ◽  
Fedir Bokhovchuk ◽  
Typhaine Martin ◽  
Clara Delaunay ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Hippo Pathway ◽  
Structural Difference ◽  
Amino Acid Motif ◽  
Structural Element ◽  
Genome Wide ◽  
Transcriptional Cofactors ◽  
New Perspective ◽  
The Hippo Pathway

AbstractThe most downstream elements of the Hippo pathway, the TEAD transcription factors, are regulated by several cofactors, such as Vg/VGLL1-3. Earlier findings on human VGLL1 and here on human VGLL3 show that these proteins interact with TEAD via a conserved amino acid motif called the TONDU domain. Surprisingly, our studies reveal that the TEAD-binding domain of Drosophila Vg and of human VGLL2 is more complex and contains an additional structural element, an Ω-loop, that contributes to TEAD binding and in vivo function. To explain this unexpected structural difference between proteins from the same family, we propose that, after the genome-wide duplications at the origin of vertebrates, the Ω-loop present in an ancestral VGLL gene has been lost in some VGLL variants. These findings illustrate how structural and functional constraints can guide the evolution of transcriptional cofactors to preserve their ability to compete with other cofactors for binding to transcription factors.

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