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Phosphatidylinositol (PI) is the precursor lipid for the minor phosphoinositides (PPIns), which are critical for multiple functions in all eukaryotic cells. It is poorly understood how phosphatidylinositol, which is synthesized in the ER, reaches those membranes where PPIns are formed. Here, we used VT01454, a recently identified inhibitor of class I PI transfer proteins (PITPs), to unravel their roles in lipid metabolism, and solved the structure of inhibitor-bound PITPNA to gain insight into the mode of inhibition. We found that class I PITPs not only distribute PI for PPIns production in various organelles such as the plasma membrane (PM) and late endosomes/lysosomes, but that their inhibition also significantly reduced the levels of phosphatidylserine, di- and triacylglycerols, and other lipids, and caused prominent increases in phosphatidic acid. While VT01454 did not inhibit Golgi PI4P formation nor reduce resting PM PI(4,5)P2 levels, the recovery of the PM pool of PI(4,5)P2 after receptor-mediated hydrolysis required both class I and class II PITPs. Overall, these studies show that class I PITPs differentially regulate phosphoinositide pools and affect the overall cellular lipid landscape.
Assuntos
Fosfatidilinositóis , Proteínas de Transferência de Fosfolipídeos , Humanos , Fosfatidilinositóis/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Proteínas de Transferência de Fosfolipídeos/genética , Metabolismo dos Lipídeos , Membrana Celular/metabolismo , Células HeLa , Organelas/metabolismo , Endossomos/metabolismo , AnimaisRESUMO
The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.
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The Hippo pathway plays a key role in development, organ size control and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator that preferentially kills YAP-dependent cancer cells. Structure-activity optimization yielded more potent MCB analogs, which led to the identification of phosphatidylinositol transfer proteins α and ß (PITPα/ß) as the direct molecular targets. We established a critical role of PITPα/ß in regulating LATS and YAP. Moreover, we showed that PITPα/ß influence the Hippo pathway via plasma membrane phosphatidylinositol-4-phosphate. This study uncovers a previously unrecognized role of PITPα/ß in Hippo pathway regulation and as potential cancer therapeutic targets.
Assuntos
Produtos Biológicos , Neoplasias , Humanos , Via de Sinalização Hippo , Fosfatidilinositóis , Proteínas de Transferência de Fosfolipídeos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.
Assuntos
Neoplasias Meníngeas , Meningioma , Neurilemoma , Animais , Humanos , Camundongos , Proliferação de Células , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Proteínas de Sinalização YAP/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Fatores de Transcrição de Domínio TEA/metabolismoRESUMO
Direct and moderation effects of swimming competence using an integrated model of self-determination theory (SDT) and theory of planned behaviour (TPB) were examined in two large-scale studies among young children. Specifically, we examined whether swimming competence had direct and moderation effects on social psychological variables of perceived need support, autonomous motivation, TPB social cognition constructs, and intention. In Study 1, using a cross-sectional survey of 4959 primary school children, swimming competence formed significant positive relationships with all model variables (ß =.061 to.330, p < .05) except intention (ß = -.009, p > .05), and its moderation effect on model parameters were small in size or not statistically significant. In Study 2, using a pre-post-test quasi-experiment among 1,609 primary school children, improvement of swimming competence was associated with change-scores in all model variables (ß =.046 to.230, p < .05) except subjective norm (ß =.049, p > .05). Swimming competence did not significantly moderate the parameter estimates of the integrated model (p > .05) at the change-score level. Findings indicate that swimming competence is associated with higher autonomous motivation; TPB social cognitions of attitude, subjective norm, and perceived behavioural control; and intention. However, swimming competence did not moderate the parameter estimates of the integrated model.
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This two-wave prospective study applied the Social Influence in Sport Model to investigate whether the social influences of parents, physical education (PE) teachers, and peers were predictive of students' intention to engage in leisure-time physical activity (PA). Participants were 2,484 secondary school students (11-18 years old) who completed a questionnaire assessing positive influence, punishment, and dysfunction from the three social agents (parents, PE teachers, and peers) at baseline, and PA intention at a 1-month follow-up. Structural equation modelling (SEM) yielded excellent goodness-of-fit and consistent pathways between the three social agents. Students' leisure-time PA intention (R2 = .103 to 0.112) was positively associated with positive influence (ß = .223 to 0.236, p < .001) and punishment (ß = .214 to 0.256, p < .01), and negatively associated with dysfunction (ß = - 0.281 to -.335, p < .001). Multi-group SEM showed that the predictions were invariant between parents, PE teachers, and peers. Furthermore, no significant differences in students' gender were found between perceived social influence and PA intention. The findings supported the application of the Social Influence in Sport Model in explaining the role of significant others on students' intention to take part in leisure-time PA.
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IL-1 signaling is adhesion-restricted in many cell types, but the mechanism that drives it is not defined. We screened for proteins recruited to nascent adhesions in IL-1-treated human fibroblasts with tandem mass tag-mass spectrometry. We used fibronectin bead preparations to enrich 10 actin-associated proteins. There was a 1.2 times log 2-fold enrichment of actin capping protein (ACP) at 30 min after IL-1 stimulation. Knockdown (KD) of ACP by siRNA reduced IL-1-induced ERK activation(by 56%, matrix metalloproteinase-3 (MMP-3) expression by 48%, and MMP-9 expression by 62% (in all reductions, P < 0.01). Confocal or structured illumination microscopy showed that ACP was diffused throughout the cytosol but strongly accumulated at the ruffled border of spreading cells. ACP colocalized with nascent paxillin- and vinculin-containing adhesions at the ruffled border, but not with mature adhesions in the center. ACP KD promoted the formation of large, stable adhesions. Immunoprecipitation and proximity ligation analysis showed that ACP was associated with the IL-1 signal transduction proteins myeloid differentiation factor 88 (MyD88) and IL-1 receptor-associated kinase (IRAK) at the ruffled border of the leading edge. IL-1-induced phospho-ERK and MyD88 or IRAK colocalized at the leading edge. We concluded that ACP is required for recruitment and function of IL-1 signaling complexes in nascent adhesions at the leading edge of the cell.-Wang, Q., Delcorde, J., Tang, T., Downey, G. P., McCulloch, C. A. Regulation of IL-1 signaling through control of focal adhesion assembly.
Assuntos
Proteínas de Capeamento de Actina/metabolismo , Fibroblastos/metabolismo , Adesões Focais/metabolismo , Interleucina-1/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Capeamento de Actina/genética , Fibroblastos/citologia , Adesões Focais/genética , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismoRESUMO
Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias/metabolismo , Comunicação Parácrina/fisiologia , Células Estromais/metabolismo , Animais , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias/genética , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor SmoothenedRESUMO
Hedgehog (Hh) signaling is critical to the patterning and development of a variety of organ systems, and both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligands, activation occurs within the stromal microenvironment. Testing whether ligand-driven Hh signaling promotes tumor angiogenesis, we found that Hh antagonism reduced the vascular density of Hh-producing LS180 and SW480 xenografts. In addition, ectopic expression of sonic hedgehog in low-Hh-expressing DLD-1 xenografts increased tumor vascular density, augmented angiogenesis, and was associated with canonical Hh signaling within perivascular tumor stromal cells. To better understand the molecular mechanisms underlying Hh-mediated tumor angiogenesis, we established an Hh-sensitive angiogenesis coculture assay and found that fibroblast cell lines derived from a variety of human tissues were Hh responsive and promoted angiogenesis in vitro through a secreted paracrine signal(s). Affymetrix array analyses of cultured fibroblasts identified VEGF-A, hepatocyte growth factor, and PDGF-C as candidate secreted proangiogenic factors induced by Hh stimulation. Expression studies of xenografts and angiogenesis assays using combinations of Hh and VEGF-A inhibitors showed that it is primarily Hh-induced VEGF-A that promotes angiogenesis in vitro and augments tumor-derived VEGF to promote angiogenesis in vivo.
Assuntos
Proteínas Hedgehog/genética , Neoplasias/genética , Neovascularização Patológica/genética , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cultura , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Nus , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neovascularização Fisiológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Patched , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/metabolismo , Células Estromais/patologia , Transplante HeterólogoRESUMO
Measuring health-related quality of life (HRQoL) is important because it can serve as an indicator or a predictor of subsequent mortality or morbidity. HRQoL has been shown to be directly related to child growth and development and indirectly related to the healthcare costs of young children. Existing measures of HRQoL in children have heavily relied on traditional questionnaires that use age-suited versions or parent proxy questionnaires. However, both of these methods may present with different types of biases and may misrepresent underlying HRQoL. The current mini reivew will first illustrate these methodological limitations and highlight the potential use of pictorial scales in addition to discussing their suitability for specifically measuring HRQoL as an alternative. We will also synthesize existing recommendations on the development of pictorial scales to provide a protocol as a recommendation to researchers who are aiming to develop an overall HRQoL pictorial scale that is suited for children.
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Saúde da Criança , Qualidade de Vida , Humanos , Criança , Inquéritos e Questionários , Psicometria , Pré-EscolarRESUMO
This study aimed to adapt and validate the Knee Osteoarthritis Fears and Beliefs Questionnaire (KOFBeQ) for Chinese patients, thereby advancing the understanding of fear-avoidance behaviors. Adopting a cross-sectional design, data were collected for 241 subjects (78.8% women; mean age 68.0 ± 7.8 years) across various healthcare settings in Hong Kong. Exploratory factor analysis resulted in an 11-item questionnaire with three distinct subscales, covering fears and beliefs related to physicians and disease (six items), daily living activities (three items), and sports and leisure activities (two items). The overall Cronbach's α coefficient was 0.86, indicating strong internal consistency. The questionnaire exhibited favorable convergent validity. Confirmatory factor analyses confirmed a good model fit. Test-retest reliability analysis indicated a high intraclass correlation coefficient of 0.93 (95% confidence interval: 0.88, 0.96), and a Bland-Altman plot revealed a slight bias in two measurements (0.97 [0.19]) without a systematic trend. The adapted Chinese version of the KOFBeQ demonstrated robust psychometric properties in terms of validity and reliability, providing an effective tool for surveying Chinese patients with knee osteoarthritis. These findings offer valuable insights for clinicians and patients, aiding in informed decision-making and improved rehabilitation strategies.
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Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
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Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Sinalização YAP/metabolismo , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasia Residual , Camundongos , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRASG12C mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the antiproliferative and proapoptotic effects of KRASG12C inhibitor (G12Ci) treatment in KRASG12C-mutant cancer cell lines. Conversely, genetic suppression of YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor-dependent mechanisms, which phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1, and MYC) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K-AKT-mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor antitumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the antitumor efficacy of KRAS-targeted therapies. SIGNIFICANCE: YAP1/TAZ-TEAD activation compensates for loss of KRAS effector signaling, establishing a mechanistic basis for concurrent inhibition of TEAD to enhance the efficacy of KRASG12C-selective inhibitor treatment of KRASG12C-mutant cancers. See related commentary by Johnson and Haigis, p. 4005.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias , Fatores de Transcrição de Domínio TEA , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transativadores/metabolismo , Proteínas de Sinalização YAP , Fatores de Transcrição de Domínio TEA/antagonistas & inibidoresRESUMO
Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Antígeno CTLA-4/genética , Biomarcadores Tumorais , Imunoterapia , Microambiente TumoralRESUMO
Non-small lung cancers (NSCLC) frequently (â¼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. SIGNIFICANCE: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005.
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Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Animais , Camundongos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MutaçãoRESUMO
Parents are often regarded as one of the significant social agents who are important to the participation of physical activity (PA) among children and adolescents. However, within the literature, the relationships between parental influences and child and adolescent PA have been inconclusive and discordant. The purpose of this meta-analysis was to quantify and synthesize the associations between parental social influences (positive parental influence, punishment, and discouragement) and the PA level of children and adolescents. Through a systematic literature search using PsycINFO, Web of Science, PubMed, ProQuest, and SPORTDiscus databases, we identified 112 eligible studies and subsequently extracted 741 effect sizes for our analysis. Multilevel meta-analysis showed that the corrected zero-order correlation of positive parental influence was positive and statistically significant, r = 0.202, SE = 0.014, t = 14.975, p < 0.001, 95% confidence interval (CI) = [0.176, 0.228]. Further moderation analysis also found that this was significantly moderated by parental gender (maternal vs. paternal), respondent of influence measure (parent-reported vs. child-reported), and type of PA measure (subjective vs. objective). The corrected zero-order correlations of negative parental influences (i.e., punishment and discouragement) were not statistically significant, and no significant moderation effects were observed. The findings of our meta-analysis showed that children and adolescents had higher PA levels when their parents supported PA participation by exerting positive social influence. Punishment and discouragement against PA by parents did not appear to be significantly associated with the PA level of children and adolescents. The findings of negative parental social influence were mixed and required further investigations.
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Exercício Físico , Relações Pais-Filho , Masculino , Humanos , Adolescente , Pai , Análise MultinívelRESUMO
Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER+ breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER+ breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers.
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Neoplasias da Mama , Receptor alfa de Estrogênio , Via de Sinalização Hippo , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.
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Mesotelioma Maligno/tratamento farmacológico , Fatores de Transcrição de Domínio TEA/antagonistas & inibidores , Animais , Proliferação de Células , Humanos , Lipoilação , Mesotelioma Maligno/genética , Camundongos , Transdução de SinaisRESUMO
Accurate segregation of chromosomes is critical to ensure that each daughter cell receives the full genetic complement. Maintenance of cohesion between sister chromatids, especially at centromeres, is required to segregate chromosomes precisely during mitosis and meiosis. The Drosophila protein MEI-S332, the founding member of a conserved protein family, is essential in meiosis for maintaining cohesion at centromeres until sister chromatids separate at the metaphase II/anaphase II transition. MEI-S332 localizes onto centromeres in prometaphase of mitosis or meiosis I, remaining until sister chromatids segregate. We elucidated a mechanism for controlling release of MEI-S332 from centromeres via phosphorylation by POLO kinase. We demonstrate that POLO antagonizes MEI-S332 cohesive function and that full POLO activity is needed to remove MEI-S332 from centromeres, yet this delocalization is not required for sister chromatid separation. POLO phosphorylates MEI-S332 in vitro, POLO and MEI-S332 bind each other, and mutation of POLO binding sites prevents MEI-S332 dissociation from centromeres.