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BACKGROUND: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response. METHODS: In this study, we used single-cell RNA-sequencing analysis of Cd45+CD11b+F4/80+ cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2+ (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation. RESULTS: We find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity. CONCLUSIONS: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.
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Macrófagos , Muramidasa , Obesidad , Receptores CCR2 , Animales , Obesidad/complicaciones , Obesidad/metabolismo , Macrófagos/metabolismo , Receptores CCR2/metabolismo , Receptores CCR2/genética , Ratones , Muramidasa/metabolismo , Muramidasa/genética , Ratones Endogámicos C57BL , Masculino , Ratones Noqueados , Transducción de Señal , Inflamación/metabolismo , Inflamación/genética , Cardiopatías/etiología , Cardiopatías/metabolismo , Cardiopatías/genéticaRESUMEN
In this issue of Cell Chemical Biology, Liu et al.1 report the identification of Q29, a synthetic diterpenoid that blocks covalent cholesterol modification of smoothened (SMO) and inhibits hedgehog signaling. Q29 is capable of suppressing tumor cell growth, both in vitro and in vivo, and overcoming resistance to SMO inhibitors.
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Colesterol , Diterpenos , Resistencia a Antineoplásicos , Proteínas Hedgehog , Receptor Smoothened , Humanos , Receptor Smoothened/antagonistas & inhibidores , Receptor Smoothened/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Colesterol/metabolismo , Colesterol/química , Diterpenos/farmacología , Diterpenos/química , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Transducción de Señal/efectos de los fármacosRESUMEN
Suppressor of fused (SUFU) is widely regarded as a key negative regulator of the sonic hedgehog (SHH) morphogenic pathway and a known tumor suppressor of medulloblastoma (MB). However, we report here that SUFU expression was markedly increased in 75% of specimens compiled in a tissue array comprising 49 unstratified MBs. The SUFU and GLI1 expression levels in this MB array showed strong positive correlation, which was also identified in a large public data set containing 736 MBs. We further report that increasing Sufu gene dosage in mice caused preaxial polydactyly, which was associated with the expansion of the Gli3 domain in the anterior limb bud and heightened Shh signaling responses during embryonic development. Increasing Sufu gene dosage also led to accelerated cerebellar development and, when combined with ablation of the Shh receptor encoded by Patched1 (Ptch1), promoted MB tumorigenesis. These data reveal multifaceted roles of SUFU in promoting MB tumorigenesis by enhancing SHH signaling. This revelation clarifies potentially counterintuitive clinical observation of high SUFU expression in MBs and may pave way for novel strategies to reduce or reverse MB progression.
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Neoplasias Cerebelosas , Meduloblastoma , Polidactilia , Ratones , Animales , Meduloblastoma/genética , Meduloblastoma/patología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Transformación Celular Neoplásica/genética , Factores de Transcripción , Neoplasias Cerebelosas/genética , Polidactilia/genéticaRESUMEN
Nitrogen is an essential macronutrient that is absorbed by roots and stored in leaves, mainly as ribulose-1,5-bisphosphate carboxylase/oxygenase1,2. During nitrogen deficiency (-N), plants activate leaf senescence for source-to-sink nitrogen remobilization for adaptative growth3-6. However, how -N signals perceived by roots are propagated to shoots remains underexplored. We found that ELF18-INDUCED LONG NONCODING RNA 1 (ELENA1) is -N inducible and attenuates -N-induced leaf senescence in Arabidopsis. Analysis of plants expressing the ELENA1 promoter ß-glucuronidase fusion gene showed that ELENA1 is transcribed specifically in roots under -N. Reciprocal grafting of the wild type and elena1 demonstrated that ELENA1 functions systemically. ELENA1 dissociates the MEDIATOR SUBUNIT 19a-ORESARA1 transcriptional complex, thereby calibrating senescence progression. Our observations establish the systemic regulation of leaf senescence by a root-derived long non-coding RNA under -N in Arabidopsis.
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Proteínas de Arabidopsis , Arabidopsis , ARN Largo no Codificante , Nitrógeno/metabolismo , Arabidopsis/metabolismo , ARN Largo no Codificante/genética , Senescencia de la Planta , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Hojas de la Planta/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Background: Colorectal cancer (CRC) is the third most common cancer worldwide and one of the leading causes of cancer-related death. Peptidomics, considered a novel branch of proteomics, has an increasing range of applications in the screening, diagnosis, prognosis, and even monitoring of cancer. However, there is little information for peptidomics analysis in CRC. Methods: In this study, a comparative peptidomic profiling was analyzed in 3 CRC tissue samples and 3 adjacent intestinal epithelial tissue samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Among the total 133 nonredundant peptides identified, 59 were significantly differentially expressed in the CRC samples and benign colonic epithelium conditions [fold change (FC) >2, P<0.05]. Totals of 25 up-regulated and 34 down-regulated peptides were detected, respectively. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to predict the possible functions of these relevant precursor proteins. To clearly identify the potential interaction network of peptide precursors, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to determine protein interactions and a possible central role in CRC. Conclusions: Our results for the first time revealed the differentially expressed peptides between the serous CRC tissue and the adjacent intestinal epithelial tissue samples, and these prominently variable peptides might have an important potential role in occurrence and development of CRC.
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Zhu and Hart1 use dual-specificity RNA aptamers to recruit cellular O-GlcNAc transferase (OGT) and induce O-GlcNAc on target proteins like ß-catenin, revealing that O-GlcNAc stabilizes ß-catenin and enhances its transcriptional activity.
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Aptámeros de Nucleótidos , N-Acetilglucosaminiltransferasas , beta Catenina , N-Acetilglucosaminiltransferasas/químicaRESUMEN
Studies in the past decade have shown that lipid droplets stored in liver cells under starvation are encapsulated by autophagosomes and fused to lysosomes via the endocytic system. Autophagy responds to a variety of environmental factors inside and outside the cell, so it has a complex signal regulation network. To this end, we first explored the role of Hedgehog (Hh) in autophagy and lipid metabolism. Treatment of normal mouse liver cells with SAG and GDC-0449 revealed elevated phosphorylation of AMP-activated protein kinase (AMPK) and increased lipidation of LC3. SAG, and GDC-0449 were agonist and antagonist of Smoothened (Smo) in canonical Hh pathway, respectively, but they played a consistent role in the regulation of autophagy in hepatocytes. Moreover, SAG and GDC-0449 did not affect the expression of glioma-associated oncogene (Gli1) and patched 1, suggesting the absence of canonical Hh signaling in hepatocytes. We further knocked down the Smo and found that the effects of SAG and GDC-0449 disappeared, indicating that the non-canonical Smo pathway was involved in the regulation of autophagy in hepatocytes. In addition, SAG and GDC-0449 promoted lipid degradation and inhibited lipid production signals. Knockdown of Smo slowed down the rate of lipid degradation rather than Sufu or Gli1, indicating that Hh signaling regulated the lipid metabolism via Smo. In summary, activates AMPK via Smo to promote autophagy and lipid degradation.
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Proteínas Quinasas Activadas por AMP , Proteínas Hedgehog , Ratones , Animales , Proteínas Hedgehog/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Hepatocitos/metabolismo , Autofagia , Lípidos , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
BACKGROUND: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. RESULTS: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-κB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-κB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. CONCLUSIONS: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy.
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The mediator complex is highly conserved in eukgaryotes and is integral for transcriptional responses. Mediator subunits associate with signal-responsive transcription factors (TF) to activate expression of specific signal-responsive genes. As the key TF of Arabidopsis thaliana senescence, ORESARA1 (ORE1) is required for nitrogen deficiency (-N) induced senescence; however, the mediator subunit that associates with ORE1 remains unknown. Here, we show that Arabidopsis MED19a associates with ORE1 to activate -N senescence-responsive genes. Disordered MED19a forms inducible nuclear condensates under -N that is regulated by decreasing MED19a lysine acetylation. MED19a carboxyl terminus (cMED19a) harbors a mixed-charged intrinsically disordered region (MC-IDR) required for ORE1 interaction and liquid-liquid phase separation (LLPS). Plant and human cMED19 are sufficient to form heterotypic condensates with ORE1. Human cMED19 MC-IDR, but not yeast cMED19 IDR, partially complements med19a suggesting functional conservation in evolutionarily distant eukaryotes. Phylogenetic analysis of eukaryotic cMED19 revealed that the MC-IDR could arise through convergent evolution. Our result of MED19 MC-IDR suggests that plant MED19 is regulated by phase separation during stress responses.
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Proteínas de Arabidopsis , Arabidopsis , Complejo Mediador , Humanos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Complejo Mediador/genética , Complejo Mediador/metabolismo , Nutrientes , Filogenia , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Facemasks as personal protective equipment play a significant role in helping prevent the spread of viruses during the COVID-19 pandemic. A desired reusable fabric facemask should strike a balance of water repellency, good filtration efficiency (FE), breathability, and mechanical robustness against washing cycles. Despite significant efforts in testing various commercial fabric materials for filtration efficiency, few have investigated fabric performance as a function of the fiber/yarn morphology and wettability of the fabric itself. In this study, we examine commercial fabrics with Janus-like behaviors to determine the best reusable fabric facemask materials by understanding the roles of morphology, porosity, and wettability of the fabric on its overall performance. We find that the outer layer of the diaper fabric consisted of laminated polyurethane, which is hydrophobic, has low porosity (â¼5%) and tightly woven yarn structures, and shows the highest overall FE (up to 54%) in the submicron particle size range (0.03-0.6 µm) among the fabrics tested. Fabric layers with higher porosity lead to lower-pressure drops, indicating higher breathability but lower FE. Tightly woven waterproof rainwear fabrics perform the best after 10 washing cycles, remaining intact morphologically with only a 2-5% drop in the overall FE in the submicron particle size range, whereas other knitted fabric layers become loosened and the laminated polyurethane thin film on the diaper fabric is wrinkled. In comparison, the surgical masks and N95 respirators made from nonwoven polypropylene (PP) fibers see over a 30% decline in the overall FE after 10 washing cycles. Overall, we find that tightly woven Janus fabrics consisting of a low porosity, a hydrophobic outer layer, and a high porosity and hydrophilic inner layer offer the best performance among the fabrics tested as they can generate a high overall FE, achieve good breathability, and maintain fabric morphology and performance over multiple washing cycles.
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OBJECTIVES: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study assessed real-world biomarker testing rates and turnaround times within a large community-based oncology network. MATERIALS AND METHODS: This retrospective observational chart review study investigated patients with mNSCLC initiating first-line (1L) systemic therapy between 01-April-2018 and 31-March-2020. Biomarker testing rates and timing relative to 1L therapy for EGFR, ALK, ROS1, BRAF, and PD-L1 were assessed, including use of next-generation sequencing (NGS). RESULTS: Among 3474 adults: 74% had adenocarcinoma and 76% had a documented ECOG performance status of 0 or 1. Ninety percent had testing for at least one biomarker, and 46% received all 5 biomarker tests. Changes in testing rates from 2018 to 2020 were 71% to 71% for EGFR, 71% to 70% for ALK, 69% to 67% for ROS1, 51% to 59% for BRAF, 82% to 84% for PD-L1, and 42% to 49% for all 5 biomarkers. NGS testing increased from 33% to 45% (p < 0.0001). Median time from mNSCLC diagnosis to 1L therapy was 35 days. Median turnaround times from biomarker testing orders to results ranged from 10 to 15 days for the individual biomarkers and 18 days for NGS. CONCLUSION: In this real-world study, while most patients received at least one biomarker test prior to 1L, <50% received all 5 tests. NGS testing also occurred in < 50% of patients but appeared to increase over time. The next phase of MYLUNG will evaluate contemporary ordering practices and turnaround times prospectively.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Antígeno B7-H1 , Biomarcadores , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Tirosina Quinasas Receptoras , Estudios RetrospectivosRESUMEN
Autophagy is a highly conservative self-digestion process to maintain intracellular homeostasis and to ensure the survival of cells under stress. Activation of Sonic Hedgehog (Shh) signaling depends on the normal endocytic degradation of pathway receptor Patched1 (Ptch1). It is unclear whether autophagy participates in the receptor endocytosis and modulates Shh signaling transduction. Here we found that blocking macroautophagy attenuates Shh signaling due to the failed transport of Smoothened (Smo) into primary cilia. At the upstream of Smo, Ptch1 was poly-ubiquitinated through K63-conjugated ubiquitin chains. Macroautophagy participates Shh-induced degradation of poly-ubiquitinated Ptch1, contributing to the activation of Shh signaling.
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Autofagia , Proteínas Hedgehog/metabolismo , Receptor Patched-1/metabolismo , Proteolisis , Animales , Células Cultivadas , Cilios/metabolismo , Células HEK293 , Humanos , Ratones , Transducción de Señal , Receptor Smoothened/metabolismo , UbiquitinaciónRESUMEN
Centrosome duplication and DNA replication are two pivotal events that higher eukaryotic cells use to initiate proliferation. While DNA replication is initiated through origin licensing, centrosome duplication starts with cartwheel assembly and is partly controlled by CP110. However, the upstream coordinator for both events has been, until now, a mystery. Here, we report that suppressor of fused protein (Sufu), a negative regulator of the Hedgehog (Hh) pathway playing a significant role in restricting the trafficking and function of glioma-related (Gli) proteins, acts as an upstream switch by facilitating CP110 phosphorylation by CDK2, promoting intranuclear Cdt1 degradation and excluding prereplication complex (pre-RC) components from chromosomes, independent of its canonical function in the Hh pathway. We found that Sufu localizes to both the centrosome and the nucleus and that knockout of Sufu induces abnormalities including centrosome amplification, increased nuclear size, multipolar spindle formation, and polyploidy. Serum stimulation promotes the elimination of Sufu from the centrosome by vesicle release at the ciliary tip and from the nucleus via protein degradation, which allows centrosome duplication and DNA replication to proceed. Collectively, this work reveals a mechanism through which Sufu negatively regulates the G1-S transition.
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Centrosoma/metabolismo , Replicación del ADN , Proteínas Represoras/metabolismo , Animales , Proteínas de Unión a Calmodulina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Muerte Celular , Núcleo Celular/metabolismo , Cilios/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Vesículas Citoplasmáticas/metabolismo , Fibroblastos/metabolismo , Fase G1 , Células HEK293 , Células HeLa , Proteínas Hedgehog/metabolismo , Humanos , Ratones , Mitosis , Mutación/genética , Fosforilación , Proteolisis , Proteínas Represoras/genética , Fase SRESUMEN
Although E3 ligase Speckle type BTB/POZ protein (SPOP) promotes tumorigenesis by acting as a key regulatory hub in clear cell renal cell carcinoma (ccRCC), the detailed molecular mechanism remains unclear. Here, we demonstrate that a well-known tumor suppressor, Suppressor of Fused (SUFU), is downregulated by SPOP. Interestingly, this downregulation depends on cullin-3(Cul3)-SPOP E3 ligase, but SUFU is not a direct substrate of SPOP. Phosphatase and tensin homolog (PTEN), a ubiquitinated substrate of SPOP, is involved in SPOP-mediated SUFU reduction. Importantly, inhibition of SUFU leads to elevated SHH and WNT signaling, consequently rescuing the reduced proliferation, migration, and invasion abilities of ccRCC cells caused by SPOP-knockdown. Moreover, combinatorial treatment with SHH and WNT inhibitors shows more effective for suppressing ccRCC cell proliferation and aggressiveness. These findings demonstrate that a novel SPOP-PTEN-SUFU axis promotes ccRCC carcinogenesis by activating SHH and WNT pathway, providing a new treatment strategy for ccRCC.
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BACKGROUND: Hedgehog signaling is essential to the regulation of embryonic development, tissue homeostasis, and stem cell self-renewal, making it a prime target for developing cancer therapeutics. Given the close link between aberrant Hedgehog signaling and cancers, many small molecular compounds have been developed to inhibit Smoothened, a key signal transducer of this pathway, for treating cancer and several such compounds have been approved by the United States Food and Drug Administration (GDC-0449 and LDE-225). However, acquired drug resistance has emerged as an important obstacle to the effective use of these first generation Hedgehog pathway blockers. Thus, new Smoothened inhibitors that can overcome such resistance is an urgent need going forward. RESULTS: We established the Smoothened/ßarrestin2-GFP high-throughput screening platform based on the mechanistic discovery of Hedgehog signaling pathway, and discovered several active small molecules targeting Smoothened including 0025A. Here we show that 0025A can block the translocation of ßarrestin2-GFP to Smoothened, displace Bodipy-cyclopamine binding to wild-type Smoothened or mutant Smoothened-D473H, reduce the accumulation of Smo on primary cilia and the expression of Gli upon Hedgehog stimulation. In addition, we show that 0025A can effectively suppress hair follicle morphogenesis and hair growth in mice. CONCLUSIONS: Our results demonstrate that 0025A is a potent antagonist targeting Smoothened wild-type and mutant receptors in the Hedgehog signaling pathway and may provide a new therapy for refractory cancers.
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BACKGROUND: Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. However, the role of long non-coding RNAs (lncRNAs), a class of crucial epigenetic regulatory molecules, has been under explored in skeletal biology. RESULTS: Here we report a young patient with short stature, hypothalamic dysfunction and mild macrocephaly, who carries a maternally inherited 690 kb deletion at Chr.1q24.2 encompassing a noncoding RNA gene, DNM3OS, embedded on the opposite strand in an intron of the DYNAMIN 3 (DNM3) gene. We show that lncRNA DNM3OS sustains the proliferation of chondrocytes independent of two co-cistronic microRNAs miR-199a and miR-214. We further show that nerve growth factor (NGF), a known factor of chondrocyte growth, is a key target of DNM3OS-mediated control of chondrocyte proliferation. CONCLUSIONS: This work demonstrates that DNM3OS is essential for preventing premature differentiation of chondrocytes required for bone growth through endochondral ossification.
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Colorectal cancer (CRC) is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients. In this study, mRNA microarray datasets GSE113513, GSE21510, GSE44076, and GSE32323 were obtained from the Gene Expression Omnibus (GEO) and analyzed with bioinformatics to identify hub genes in CRC development. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Gene ontology (GO) and KEGG analyses were performed through the DAVID database. STRING database and Cytoscape software were used to construct a protein-protein interaction (PPI) network and identify key modules and hub genes. Survival analyses of the DEGs were performed on GEPIA database. The Connectivity Map database was used to screen potential drugs. A total of 865 DEGs were identified, including 374 upregulated and 491 downregulated genes. These DEGs were mainly associated with metabolic pathways, pathways in cancer, cell cycle and so on. The PPI network was identified with 863 nodes and 5817 edges. Survival analysis revealed that HMMR, PAICS, ETFDH, and SCG2 were significantly associated with overall survival of CRC patients. And blebbistatin and sulconazole were identified as candidate drugs. In conclusion, our study found four hub genes involved in CRC, which may provide novel potential biomarkers for CRC prognosis, and two potential candidate drugs for CRC.
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Reversible phosphorylation of Suppressor of fused (Sufu) is essential for Sonic Hedgehog (Shh) signal transduction. Sufu is stabilized under dual phosphorylation of protein kinase A (PKA) and glycogen synthase kinase 3ß (GSK3ß). Its phosphorylation is reduced with the activation of Shh signaling. However, the phosphatase in this reversible phosphorylation has not been found. Taking advantage of a proteomic approach, we identified Protein phosphatase 4 regulatory subunit 2 (Ppp4r2), an interacting protein of Sufu. Shh signaling promotes the interaction of these two proteins in the nucleus, and Ppp4 also promotes dephosphorylation of Sufu, leading to its degradation and enhancing the Gli1 transcriptional activity. Finally, Ppp4-mediated dephosphorylation of Sufu promotes proliferation of medulloblastoma tumor cells, and expression of Ppp4 is positively correlated with up-regulation of Shh pathway target genes in the Shh-subtype medulloblastoma, underscoring the important role of this regulation in Shh signaling.