Regulates Organ Size Research Articles

SET DOMAIN GROUP 711-mediated H3K27me3 methylation of cytokinin metabolism genes regulates organ size in rice.

Organ size shapes plant architecture during rice (Oryza sativa) growth and development, affecting key factors influencing yield, such as plant height, leaf size, and seed size. Here, we report that the rice Enhancer of Zeste [E(z)] homolog SET DOMAIN GROUP 711 (OsSDG711) regulates organ size in rice. Knockout of OsSDG711 produced shorter plants with smaller leaves, thinner stems, and smaller grains. We demonstrate that OsSDG711 affects organ size by reducing cell length and width and increasing cell number in leaves, stems, and grains. The result of chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) using an antitrimethylation of histone H3 lysine 27 (H3K27me3) antibody showed that the levels of H3K27me3 associated with cytokinin oxidase/dehydrogenase genes (OsCKXs) were lower in the OsSDG711 knockout line Ossdg711. ChIP-qPCR assays indicated that OsSDG711 regulates the expression of OsCKX genes through H3K27me3 histone modification. Importantly, we show that OsSDG711 directly binds to the promoters of these OsCKX genes. Furthermore, we measured significantly lower cytokinin contents in Ossdg711 plants than in wild-type plants. Overall, our results reveal an epigenetic mechanism based on OsSDG711-mediated modulation of H3K27me3 levels to regulate the expression of genes involved in the cytokinin metabolism pathway and control organ development in rice. OsSDG711 may be an untapped epigenetic resource for ideal plant type improvement.

Development of LM-41 and AF-2112, two flufenamic acid-derived TEAD inhibitors obtained through the replacement of the trifluoromethyl group by aryl rings

The Hippo pathway regulates organ size and tissue homeostasis by controlling cell proliferation and apoptosis. The YAP–TEAD transcription factor, the downstream effector of the Hippo pathway, regulates the expression of genes such as CTGF, Cyr61, Axl and NF2. Aberrant Hippo activity has been identified in multiple types of cancers. Flufenamic acid (FA) was reported to bind in a liphophilic TEAD palmitic acid (PA) pocket, leading to reduction of the expression of Axl and NF2. Here, we show that the replacement of the trifluoromethyl moiety in FA by aromatic groups, directly connected to the scaffold or separated by a linker, leads to compounds with better affinity to TEAD. Co-crystallization studies show that these compounds bind similarly to FA, but deeper within the PA pocket. Our studies identified LM-41 and AF-2112 as two TEAD binders that strongly reduce the expression of CTGF, Cyr61, Axl and NF2. LM-41 gave the strongest reduction of migration of human MDA-MB-231 breast cancer cells.

Genome-wide analysis of KIX gene family for organ size regulation in soybean (Glycine max L.).

The KIX domain, conserved among various nuclear and co-activator factors, acts as a binding site that interacts with other transcriptional activators and co-activators, playing a crucial role in gene expression regulation. In plants, the KIX domain is involved in plant hormone signaling, stress response regulation, cell cycle control, and differentiation, indicating its potential relevance to crop productivity. This study aims to identify and characterize KIX domains within the soybean (Glycine max L.) genome to predict their potential role in improving crop productivity. The conservation and evolutionary history of the KIX domains were explored in 59 plant species, confirming the presence of the KIX domains in diverse plants. Specifically, 13 KIX domains were identified within the soybean genome and classified into four main groups, namely GmKIX8/9, GmMED15, GmHAC, and GmRECQL, through sequence alignment, structural analysis, and phylogenetic tree construction. Association analysis was performed between KIX domain haplotypes and soybean seed-related agronomic traits using re-sequencing data from a core collection of 422 accessions. The results revealed correlations between SNP variations observed in GmKIX8-3 and GmMED15-4 and soybean seed phenotypic traits. Additionally, transcriptome analysis confirmed significant expression of the KIX domains during the early stages of soybean seed development. This study provides the first characterization of the structural, expression, genomic haplotype, and molecular features of the KIX domain in soybean, offering a foundation for functional analysis of the KIX domain in soybean and other plants.

Genetic mapping and transcriptome profiling of a chickpea (Cicer arietinum L.) mutant identifies a novel locus (CaEl) regulating organ size and early vigor.

Chickpea is among the top three legumes produced and consumed worldwide. Early plant vigor, characterized by good germination and rapid seedling growth, is an important agronomic trait in many crops including chickpea, and shows a positive correlation with seed size. In this study, we report a gamma-ray-induced chickpea mutant with a larger organ and seed size. The mutant (elm) exhibits increased early vigor and contains higher proline that contributes to a better tolerance under salt stress at germination, seedling, and early vegetative phase. The trait is governed as monogenic recessive, with wild-type allele being incompletely dominant over the mutant. Genetic mapping of this locus (CaEl) identified it as a previously uncharacterized gene (101503252) in chromosome 1 of the chickpea genome. There is a deletion of this gene in the mutant with a complete loss of expression. In silico analysis suggests that the gene is present as a single copy in chickpea and related legumes of the galegoid clade. In the mutant, cell division and expansion are affected. Transcriptome profiling identified differentially regulated transcripts related to cell division, expansion, cell wall organization, and metabolism in the mutant. The mutant can be exploited in chickpea breeding programs for increasing plant vigor and seed size.

Ca2+ signaling and the Hippo pathway: Intersections in cellular regulation

The Hippo signaling pathway is a master regulator of organ size and tissue homeostasis. Hippo integrates a broad range of cellular signals to regulate numerous processes, such as cell proliferation, differentiation, migration and mechanosensation. Ca2+ is a fundamental second messenger that modulates signaling cascades involved in diverse cellular functions, some of which are also regulated by the Hippo pathway. Studies published over the last five years indicate that Ca2+ can influence core Hippo pathway components. Nevertheless, comprehensive understanding of the crosstalk between Ca2+ signaling and the Hippo pathway, and possible mechanisms through which Ca2+ regulates Hippo, remain to be elucidated. In this review, we summarize the multiple intersections between Ca2+ and the Hippo pathway and address the biological consequences.

Abstract P3037: MicroRNA-205 Is Required For Normal Cell Cycle And Cardiac Growth In The Neonatal Mouse Heart.

After birth, most newborn mouse cardiomyocytes (CM) undergo a final cycle of cell division in the absence of cytokinesis, which leads to binucleation. The majority of subsequent increases in cardiac mass are attributable to cardiomyocyte hypertrophy, as a negligible number of new CM are created after birth. Mice with a heart-specific deletion of Dicer, a crucial enzyme necessary for microRNA maturation, die by the fifth postnatal day in spite of having normal cardiac morphology and function at birth. Despite the significance of this phenomenon, little is known about the molecular/genetic foundation for the change from hyperplastic to hypertrophic-based myocardial expansion that occurs in the neonatal mouse heart. We hypothesize that a microRNA is required for the normal transition from fetal to adult heart during the neonatal period. Heart microRNA profiles (3 arrays/time point) were measured from RNA was isolated from E19, 1, 3, 5, 7, 10, and 35-day-old mouse hearts (9 hearts/time point pooled). Bioinformatic analysis identified microRNA-205 as a possible participant in the cardiac transitional program. We observed a transient 20-fold increase in miR205 expression between postnatal days 1 and 5, with levels returning to baseline by day 10. In-situ hybridization revealed miR-205 expression is restricted to the heart's epicardium.We next generated mice with a CM-specific deletion of miR205 using MHCcre targeting of a floxed-miR205 allele. Mice lacking miR-205 in their CM appear normal at birth. Elevated cell cycle markers (Ki67 & phospho-pH3) were detected at postnatal day-14 with 20% larger hearts at postnatal day 14, and adult hearts measuring up to 50% larger than controls. In contrast, a CM-specific miR205 over-expression mouse model resulted in more CM being present at both 5-day and 14-day post-birth. Interestingly, no difference in cell-cycle markers or heart size was observed. miR205 directly targets YAP within the evolutionarily conserved hippo pathway, which regulates organ size. YAP protein expression is significantly increased in hearts lacking miR205. Both of the miR205-heart models present with altered Hippo signaling kinetics after birth. We conclude that miR205 regulates postnatal heart size by directly modulating the Hippo pathway.

The MIO1-MtKIX8 module regulates the organ size in Medicago truncatula.

Plant organ size is an important agronomic trait tightly related to crop yield. However, the molecular mechanisms underlying organ size regulation remain largely unexplored in legumes. We previously characterized a key regulator F-box protein MINI ORGAN1 (MIO1)/SMALL LEAF AND BUSHY1 (SLB1), which controls plant organ size in the model legume Medicago truncatula. In order to further dissect the molecular mechanism, MIO1 was used as the bait to screen its interacting proteins from a yeast library. Subsequently, a KIX protein, designated MtKIX8, was identified from the candidate list. The interaction between MIO1 and MtKIX8 was confirmed further by Y2H, BiFC, split-luciferase complementation and pull-down assays. Phylogenetic analyses indicated that MtKIX8 is highly homologous to Arabidopsis KIX8, which negatively regulates organ size. Moreover, loss-of-function of MtKIX8 led to enlarged leaves and seeds, while ectopic expression of MtKIX8 in Arabidopsis resulted in decreased cotyledon area and seed weight. Quantitative reverse-transcription PCR and in situ hybridization showed that MtKIX8 is expressed in most developing organs. We also found that MtKIX8 serves as a crucial molecular adaptor, facilitating interactions with BIG SEEDS1 (BS1) and MtTOPLESS (MtTPL) proteins in M. truncatula. Overall, our results suggest that the MIO1-MtKIX8 module plays a significant and conserved role in the regulation of plant organ size. This module could be a good target for molecular breeding in legume crops and forages.

Transcriptional and phytohormone regulatory network involved in LITTLELEAF-mediated organ size development in cucumber (Cucumis sativus)

Organ size, especially fruit size, is an economically important trait in many horticulture crops like cucumber (Cucumis sativus L.) which affects both fruit yield and quality. Organ size determination is the outcome of complex interplay of many factors such as transcription regulators, phytohormone and the environments. The cucumber littleleaf (ll) mutation exhibits small organ size, which encodes a defective WD40 repeat domain-containing protein, but the regulatory mechanisms of LL-dependent organ size control are largely unknown. To test the functions of the ll gene in different genetic backgrounds and explore its regulatory network, we developed near isogenic lines (NIL) of ll gene by introgressing the recessive allele into a Chinese Long inbred line 9930 with marker assisted selection (MAS). Both foreground and background selections were practiced which allowed development of a NIL (HAULL) at BC2F2 which were homologous at the ll locus and captured >96% genetic background of the recurrent parent. Comparative morphological analysis between the NILs indicated that the mutant allele for reduced organ size was independent of the genetic background. Transcriptome profiling using RNA-Seq in the unpollinated ovaries of the two NILs identified differentially expressed genes which were highly enriched with genes known to regulate organ size, as well as transcription factors, and genes in various phytohormone biosynthesis/signaling pathways. RNA-Seq and phytohormone assays found that auxin and cytokinin played more important roles in LL-regulated fruit growth. These results will be helpful for further explore the molecular mechanism of organ size in cucumber.

Hydroalcoholic Extract of Achillea Wilhelmsii Decreases the Expressions of Hippo Signaling Pathway-Associated Oncogenes in the A549 Lung Cancer Cell Line

Background: Achillea wilhelmsii used in traditional Iranian medicine to treat a variety of disorders, has been proven to contribute to some signaling pathways in cancers. Evidence suggests that the Hippo pathway, which regulates organ size, is altered in a few conditions like lung cancer. In this regard, this study aimed to evaluate the effect of the hydroalcoholic extract of this plant on the viability and mRNA expression of some Hippo signaling pathway-associated oncogenes and suppressors in A549 lung cancer cell lines. Methods: Hydroalcoholic extract was prepared using a Soxhlet extractor and its antiproliferative activity was studied by MTT assay. Then, the mRNA expressions of "large tumour suppressor kinases 1 and 2" (LATS1 and LATS2), "Yes1 Associated Transcriptional Regulator" (YAP1), and "Transcriptional co‑activator with PDZ‑binding motif" (TAZ) were measured using real-time PCR. Results: According to MTT, the viability was decreased significantly after 24 h treatment with A. wilhelmsii at the concentrations of 800-1000 μg/ml and after 48 h treatment at the concentration of 400- 1000 μg/ml. While the mRNA levels of LATS1, TAZ, and YAP1 decreased significantly compared to untreated cells at the concentration of 200 μg/ml after 48 h treatment. However, the mRNA expression of LATS2 did not change. Conclusion: Our findings showed that hydroalcoholic extract of A. wilhelmsii inhibited the viability of lung cancer cells as well as it could decrease the expression of both oncogenes in the Hippo pathway. However, it had suppressing effects on LATS1, which should be considered in further studies. conclusion: Hydroalcoholic extract of A. wilhelmsii might inhibit proliferation of lung cancer cells as well as it could decrease the expression of both oncogenes in them. However, it had suppressing effects on LATS1, which should be considered in further studies.

The functional relationship of Yap/Taz with autophagy functions in sarcopenia associated with aging

BACKGROUND: Muscle loss is one of the features associated with aging with significant impacts on the quality of life. Yap/Taz, the effectors of the Hippo pathway, was shown to regulate organ size and may be associated with aging. We postulate that Yap/Taz modulation may play a role in maintaining muscle fiber size or mediating the function of autophagy during aging and sarcopenia. OBJECTIVE: The research aim to explore sarcopenia and its relationship to autophagy and Yap/Taz expression. Additionally, we also explored the relationship of autophagy function and Yap/Taz on skeletal muscle tissue during aging. METHODS: We conducted experiments on two groups of rats kept at 16 and 80 weeks. Skeletal muscle tissue from the soleus muscle was harvested, and mRNA expression of Yap/Taz and genes associated with the autophagy pathway were quantified. Immunoblotting was done with antibodies against Yap/Taz and autophagy proteins. Bafilomycin and Verteporfin were used on the C2C12 cell line to elucidate the interaction between autophagy and Yap/Taz. RESULTS: Old rats were found to have a smaller fiber surface area of the soleus muscle and was associated with increased Yap mRNA and protein expression. The inhibition of autophagy increased Yap levels. However, the inhibition of Yap/Taz function did not affect autophagy in skeletal muscle. CONCLUSIONS: With current evidence, increased Yap was paradoxically associated with sarcopenia, and this increase was caused by the decreased autophagic flux caused by aging.

YAP promotes AP-1 expression in tubular epithelial cells in the kidney.

Chronic kidney disease (CKD) is a major health problem. Kidney fibrosis is a hallmark and final common pathway of CKD. The Hippo/yes-associated protein (YAP) pathway regulates organ size, inflammation, and tumorigenesis. Our previous study demonstrated tubular YAP activation by tubule-specific double knockout of mammalian STE20-like protein kinase 1/2 (Mst1/2) induced CKD in mice, but the underlying mechanisms remain to be fully elucidated. Activator protein (AP)-1 activation was found to promote tubular atrophy and tubulointerstitial fibrosis. Therefore, we studied whether YAP regulates AP-1 expression in the kidney. We found that expression of various AP-1 components was induced in kidneys subjected to unilateral ureteric obstruction and in Mst1/2 double knockout kidneys, and these inductions were blocked by deletion of Yap in tubular cells, with Fosl1 being most affected compared with other AP-1 genes. Inhibition of Yap also most highly suppressed Fosl1 expression among AP-1 genes in HK-2 and IMCD3 renal tubular cells. YAP bound to the Fosl1 promoter and promoted Fosl1 promoter-luciferase activity. Our results suggest that YAP controls AP-1 expression and that Fosl1 is the primary target of YAP in renal tubular cells.NEW & NOTEWORTHY Yes-associated protein (YAP) activation leads to tubular injury, renal inflammation, and fibrosis, but the underlying mechanisms are not fully understood. We now provide genetic evidence that YAP promotes activator protein-1 expression and that Fosl1 is the primary target of YAP in renal tubular cells.

YAP regulates the liver size during the fasting-refeeding transition in mice.

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

Two Hippo signaling modules orchestrate liver size and tumorigenesis.

The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.

Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration.

YAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitutive active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible 'closed' chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.

BnaMPK3s promote organ size by interacting with BnaARF2s in Brassica napus.

BnaMPK3s promote organ size by interacting with BnaARF2s in Brassica napus.

The centralspindlin complex regulates cytokinesis and morphogenesis in the C. elegans spermatheca.

Organ morphogenesis needs orchestration of a series of cellular events, including cell division, cell shape change, cell rearrangement and cell death. Cytokinesis, the final step of cell division, is involved in the control of organ size, shape and function. Mechanistically, it is unclear how the molecules involved in cytokinesis regulate organ size and shape. Here, we demonstrate that the centralspindlin complex coordinates cell division and epithelial morphogenesis by regulating cytokinesis. Loss of the centralspindlin components CYK-4 and ZEN-4 disrupts cell division, resulting in altered cell arrangement and malformation of the Caenorhabditis elegans spermatheca. Further investigation revealed that most spermathecal cells undergo nuclear division without completion of cytokinesis. Germline mutant-based analyses suggest that CYK-4 regulates cytokinesis of spermathecal cells in a GTPase activator activity-independent manner. Spermathecal morphology defects can be enhanced by double knockdown of rho-1 and cyk-4, and partially suppressed by double knockdown of cdc-42 and cyk-4. Thus, the centralspindlin components CYK-4 and ZEN-4, together with RHO-1 and CDC-42, are central players of a signaling network that guides spermathecal morphogenesis by enabling completion of cytokinesis.

Comprehensive analysis of CYP78A family genes reveals the involvement of <i>CYP78A5</i> and <i>CYP78A10</i> in fruit development in eggplant

CYP78A family is a plant-specific family, members of which have been considered as promising targets for yield improvement due to their important roles in regulating organ size. Eggplant is an important vegetable cultivated worldwide. However, little information about the eggplant CYP78As (SmCYP78As) limits the potential utilization of SmCYP78As for crop improvement. In this study, we identified six CYP78A genes in eggplant genome and named <italic>SmCYP78A5</italic> to <italic>SmCYP78A10</italic> according to the phylogenetic relationships to Arabidopsis CYP78As. The phylogenetic analysis of CYP78As from eggplant, Arabidopsis, rice and tomato classified the 27 CYP78As into five clades. SmCYP78As were found in three of the five clades. This classification is consistently supported by their gene structures, domains and conserved motifs. Segmental duplication events were found to contribute the expansion of the SmCYP78A family. Comparative syntenic analysis provided further insight into the phylogenetic relationships of CYP78A genes from the four plants. qRT-PCR analysis revealed that the expression of the six SmCYP78As was detected in at least one of the eight tissues, showing a tissue-specific pattern. Notably, SmCYP78A5 and SmCYP78A10 were highly expressed in developing ovaries, indicating the involvement of fruit development in eggplant. Co-expression clustering and GO enrichment analysis suggested that <italic>SmCYP78A5</italic> and <italic>SmCYP78A10</italic> regulate fruit development likely through different pathways. In addition, six transcription factors were identified as promising candidates that may directly bind promoters of <italic>SmCYP78A5</italic> and <italic>SmCYP78A10</italic>. This study provides a comprehensive overview of the SmCYP78As family, which would lay a foundation for further understanding of evolution and function of SmCYP78A family.

YAP regulates intestinal epithelial cell proliferation through activation of STAT3 in DSS-induced colitis and associated cancer.

Ulcerative colitis (UC) is a chronic, relapsing inflammation of the colon. Impaired epithelial repair is an important biological features of UC. Accelerating intestinal epithelial repair to achieve endoscopic mucosal healing has become a key goal in UC. Yes-associated protein (YAP) is a key transcriptional coactivator that regulates organ size, tissue growth and tumorigenesis. Growing studies have focused on the role of YAP in intestinal epithelial regeneration. This study explore the molecular mechanism for the role YAP in modulating colonic epithelial proliferation, repair, and the development of colitis associated cancer. We constructed the acute colitis mouse model through successive 5 days of 3% dextran sulfate sodium salt (DSS) induction. Then YAP-overexpressed mouse model was constructed by intraperitoneal injection the YAP overexpressed and negative control lentivirus into DSS mice. On the 5th day of DSS induction and the 5th day of normal drinking water after removing DSS (5+5 d), the mice were killed by spinal dislocation. The colon was taken to measure the length, and the bowel 1-2 cm near the anal canal was selected for immunohistochemical and Western blotting. We used YAP over-expressed colonic epithelial cells and small interfering signal transducer and activator of transcription 3 (STAT3) RNA to probe the regulation of YAP on STAT3, using cell counting kit-8 and scratch assays to explore the role of YAP on colonic epithelial cell proliferation. Finally, we conducted co-immunoprecipitation to test the relationship between YAP and STAT3. After DSS treatment, the expression of YAP was dramatically diminished in crypts. Compared with the empty control mice, overexpression of YAP drastically accelerated epithelial regeneration after DSS induced colitis, presenting with more intact of structural integrity in intestinal epithelium and a reduction in the number of inflammatory cells in the mucosa. Further Western blotting, functional experiment and co-immunoprecipitation analyses showed that the expression of YAP in nucleus was significantly increased by 2 h post DSS cessation, accompanied with up-regulated total protein levels of STAT3 and phosphorylated-STAT3 (p-STAT3). Overexpression of YAP enhanced the expression of STAT3, p-STAT3, and their transcriptional targets including c-Myc and Cyclin D1. In addition, it promoted the proliferation and the "wound healing" of colonic cells. However, these effects were reversed when silencing STAT3 on YAP-overexpressed FHC cells. Moreover, protein immunoprecipitation indicated that YAP could directly interact with STAT3 in the nucleus, up-regulatvng the expressvon of STAT3. Finally, during the process of CAC, overexpression of YAP mutant caused the down-regulated expression of STAT3 and inhibited the development and progress of CAC. YAP activates STAT3 signaling in regulation of epithelial cell proliferation and promotes mucosal regeneration after DSS induced colitis, which may serve as a potential therapeutic target in UC. However, persistent and excessive YAP activation may promote CAC development.

Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma.

The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm.

Genome-wide association study provides genetic insights into natural variation in watermelon rind thickness and single fruit weight.

Rind thickness and fruit weight are agronomic traits closely related to quality and yield, which have attracted much attention from consumers and breeders. However, the genetic mechanism of these two traits is still not well understood in natural populations. In this study, rind thickness and single fruit weight in 151 watermelon accessions were determined in 2019 and 2020, and genome-wide association analysis was performed by integrating phenotypic and genotype data. Abundant phenotypic variation was found in the test population, and the watermelon with thinner rind thickness tended to have smaller fruit weights. Five significant SNPs were closely associated with rind thickness on chromosome 2 by Genome-wide association study (GWAS), i.e., 32344170, 32321308, 32304738, 32328501, and 32311192. And there were 21 genes were annotated in the candidate interval, most notably, Cla97C02G044160 belonged to the MADS family, and part of the genes in this family played an important role in regulating organ size, further analysis of gene structure, gene expression level, and phylogenetic tree showed that Cla97C02G044160 was a candidate gene for regulating target traits. In conclusion, our study provides molecular insights into the natural variation of watermelon rind thickness and single fruit weight, meanwhile, providing data support for molecular marker-assisted breeding.