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Results for “Pathway analysis”

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At least 19 recordsLinked to original sources

PubMed2026

Subphenogroups of acute heart failure with preserved ejection fraction: comprehensive proteomics and pathway analysis.

BACKGROUND: Heterogeneity of heart failure with preserved ejection fraction (HFpEF) results in significant challenges for treatment development. Identifying and characterising distinct HFpEF phenogroups may aid in tailoring therapeutic strategies for these patients. The objective of this study was to assess proteomic patterns of HFpEF phenogroups identified through a machine-learning-based clustering model, with the aim of uncovering specific biological pathways associated with each phenogroup. METHODS: This study represents a post-hoc analysis of the ongoing Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a multicentre prospective observational study of hospitalised patients with acute decompensated HFpEF. Of the overall cohort (N=1238), this study analysed 198 patients with HFpEF with available proteomics data. These patients were classified into four phenogroups using the machine-learning-based clustering model. The SomaScan assay V.4.1 was used to measure levels of >7000 plasma proteins, and subsequent pathway analysis was conducted to determine the biological differences among the phenogroups. RESULTS: We identified four distinct phenogroups: Phenogroup 1 ('rhythm trouble'), Phenogroup 2 ('ventricular-arterial uncoupling'), Phenogroup 3 ('low output and systemic congestion') and Phenogroup 4 ('systemic failure'). The proteomics revealed distinct protein expression profiles among the phenogroups, with ribonuclease 4, tax1-binding protein 1, regenerating islet-derived protein 3-gamma and alpha-1-antichymotrypsin being the most significant markers to specific identified phenogroups. Pathway analysis suggested differences in immune response, autonomic activation, cellular homeostasis and tissue repair mechanisms across the phenogroups. CONCLUSIONS: Using a comprehensive plasma proteomics approach, our study identified distinct proteomic profiles of HFpEF phenogroups, which in turn suggest specific underlying biological processes. These profiles suggest the involvement of inflammatory activation, tissue injury and regenerative responses, immune modulation and systemic stress signalling as key components of HFpEF pathophysiology. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Humans↗

PubMed2025

Gene and pathway analysis of genome-wide genetic associations of bladder cancer.

BACKGROUND: Although genetic variants associated with bladder cancer (BCa) risk have been identified through hypothesis-driven and genome-wide association studies, a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved. MATERIALS AND METHODS: In this 2-stage functional genomics study, we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics, followed by a meta-analysis of gene-level significance p values, to obtain a consensus gene ranking in terms of association with BCa. Subsequently, we performed preranked gene-set enrichment analysis to identify the functional pathways involved in BCa genetic susceptibility. Joint analysis with gene-set enrichment analysis, based on somatic alteration frequency, was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa. RESULTS: Other than the well-known BCa genes (such as FGFR3, MYC, TERT, CCNE1, and TP63), we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development, including SETD2, a possible tumor suppressor gene involved in chromatin remodeling. We further demonstrated convergence between genetic associations and somatic alterations at both the gene (eg, FGFR3 and TERT) and pathway levels (eg, cell cycle and chromatin modification), as well as functional ontologies specifically implicated in germline predisposition to BCa (eg, CD8/TCR signaling, immune checkpoints, and cytokine signaling). CONCLUSIONS: We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the development of BCa by affecting antitumor immunity, response to toxic exposure, and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.

Bladder cancer↗

PubMed2026

Comprehensive Genomic Profiling Timeliness Beyond Laboratory Turnaround Time: A Patient-Facing Pathway Analysis.

AIM: We evaluated the timeliness of the patient-facing comprehensive genomic profiling (CGP) pathway by separating laboratory and post-laboratory intervals within an expert panel-mediated process, using direct disclosure of results to patients as the endpoint. METHODS: This single-center retrospective study included adult CGP test episodes performed under government-funded cancer genomic medicine at a Japanese university hospital between October 2019 and November 2025. The primary outcome was patient-centered turnaround time (TAT), defined as the interval from informed consent to direct disclosure of the CGP result to the patient. Laboratory TAT and pathway intervals were summarized descriptively, and laboratory TAT was compared across assays. RESULTS: Among 882 CGP test episodes, median laboratory TAT was 14 days (interquartile range [IQR], 12-16) among 871 evaluable episodes. Among 828 evaluable episodes, median patient-centered TAT was 41 days (IQR 35-45). The laboratory analysis retained observed long intervals, including a maximum of 72 days; no episode was excluded solely because laboratory TAT exceeded 56 days. These findings indicate that laboratory TAT was only one component of the longer consent-to-disclosure pathway. CONCLUSION: In this routine-care CGP pathway, patient-facing timeliness depended on the full process from consent to direct patient disclosure. Patient-centered TAT should be monitored alongside laboratory TAT as a care-delivery measure.

comprehensive genomic profiling↗

PubMed2026

Global downstream BMP15 pathway analysis in human ovarian granulosa cells reveals novel genetic variations associated with primary ovarian insufficiency.

OBJECTIVES: Primary ovarian insufficiency (POI) is a fertility disorder with a well-established genetic component, but many cases still remain idiopathic. Approximately 1.5-12% of patients with POI can carry a variant in the BMP15 gene, depending on the population and the diagnostic criteria. We hypothesize that genetic variations within pathways downstream of BMP15 activity in ovarian granulosa cells (GCs) may contribute to unexplained cases of POI. The main goal of this study is to identify novel variants associated with POI in genes induced by BMP15 in GCs. STUDY DESIGN: Primary cultures of human GCs were stimulated with recombinant human BMP15. Microarray analysis profiled the BMP15-induced transcriptome in GCs. Validation was achieved by qPCR and immunoblot. Further, target exome sequencing of the differentially expressed genes was performed on 64 women with early POI onset in search of novel variants. MAIN OUTCOME MEASURES: Transcriptome profiling of human GCs stimulated with BMP15 and target exome sequencing in women with early onset of POI. RESULTS: Transcriptome analysis revealed significant upregulation of 19 genes (p < 0.05). Ontology analysis of these genes converged towards two main pathways: TGF-beta signaling and regulation of stem cell pluripotency. Target exome sequencing identified six novel rare variants in five BMP15-induced genes (SAMD11, SMAD6, ID1, USP35, GPCR137C) in 9 of the 64 women with early POI (14%). CONCLUSIONS: BMP15 action in human ovarian GCs defines TGF-beta signaling and pluripotency fate in ovarian follicles. In addition, this study uncovers new potential candidate genes for the pathogenesis of POI.

Humans↗

PubMed2026

Virtual reality physical education and adolescents' exercise interest and physical fitness: An explanatory sequential mixed-methods randomized trial with exploratory pathway analysis.

Traditional physical education (PE) faces declining student interest and limited fitness gains. Virtual reality (VR) offers immersive, gamified experiences, but evidence regarding its effectiveness and explanatory pathways remains limited. This explanatory sequential mixed-methods randomized trial assigned 360 adolescents (aged 13-16) from three middle schools to either VR-supported PE (n = 180) or conventional PE (n = 180) for 12 weeks, with a 4-week follow-up. Outcomes included exercise interest (validated scale), physical fitness (coordination via MABC-2, cardiorespiratory endurance via the 20-m shuttle run, explosive power via the standing long jump, and speed via the 10-m sprint), and accelerometer-measured physical activity. The qualitative component involved 38 unique students: 32 completed individual semi-structured interviews, and six additional students participated only in focus groups. Three-level linear mixed-effects models and exploratory structural equation modeling were used. The VR group showed significantly greater improvements in exercise interest (d = 0.78), coordination (d = 0.62), cardiorespiratory endurance (d = 0.55), and speed (d = 0.48) than the control group (all p < 0.001), but not in explosive power (d = 0.12, p = 0.148). Effects were partially retained at follow-up (interest d = 0.65, coordination d = 0.48, endurance d = 0.42, and speed d = 0.30), a pattern not fully consistent with a purely novelty-driven explanation. Exploratory mediation identified exercise interest as a statistically compatible explanatory pathway (indirect effect = 0.34, 95% CI [0.22, 0.46]), although the timing of measurement precludes causal interpretation. Qualitative findings contextualized these results by highlighting immersion, feedback, self-efficacy, and perceived transfer. VR-supported PE may enhance adolescents' exercise interest and selected fitness dimensions, but its limited effect on explosive power and possible novelty contribution indicate that it should complement, rather than replace, conventional PE. Longer-term studies are needed.

Humans↗

PubMed2026

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis.

BACKGROUND: Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied. METHODS: A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers. RESULTS: Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR = 1.29 [1.18-1.42]), diabetes (HR = 1.25 [1.13-1.38]) and chronic obstructive pulmonary disease (COPD) (HR = 1.74 [1.50-2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR = 1.45 [1.03-2.05]), diabetes (OR = 1.01 [1.01-1.02]) and COPD (OR = 1.04 [1.02-1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions. CONCLUSIONS: Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged ≤55 years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

Humans↗

PubMed1977

Mutations affecting genetic recombination in bacteriophage T4D. I. Pathway analysis.

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Alleles↗

PubMedDate not supplied

Snell's Law: optimum pathway analysis.

An analysis is made of the various possible paths traveling from one medium to another. It is demonstrated that the most efficient possible path for traveling in the shortest possible time is the path determined by Snell's Law. Conversely, when light is refracted as it passes from one medium to another, it is completing the trip in the minimum possible time, less time than if it had passed through the various media in a straight line.

Humans↗

PubMed1992

Pathway analysis of protein electron-transfer reactions.

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Amino Acid Sequence↗

PubMed1991

[Effects of stimulation of arcuate nucleus on intragastric pressure and peripheral pathway analysis in rats].

The effect of electrical stimulation of arcuate nucleus (ARC) on intragastric pressure (IGP) was examined on 68 Wistar rats anaesthetized with urethan. The results were as follows: (1) Stimulation of ARC could induce an obvious decrease of IGP. (2) This effect was not blocked by atropine but partially by vagotomy. (3) Extirpation of celiac neural plexus or intramuscular injection of phentolamine could obviously reduce the suppression of IGP induced by ARC stimulation, but intramuscular injection of propranolol had no such effect. (4) After vagotomy plus extirpation of celiac neural plexus, IGP could still be made a decrease by stimulating ARC. In view of the present investigation, it is suggested that (1) Both sympathetic nerve and vagus are involved in the reduction of IGP induced by ARC stimulation, the former and the latter routes being respectively mediated by alpha-adrenoceptor and non-cholinergic, non-adrenergic fibres. (2) Humoral factors may be also involved in this effect of ARC stimulation.

Animals↗

PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗

PubMed2025

Association Analysis of the Circulating Proteome With Sarcopenia-Related Traits Reveals Potential Drug Targets for Sarcopenia.

BACKGROUND: Sarcopenia severely affects the physical health of the elderly. Currently, there is no specific drug available for sarcopenia. This study aims to identify pathogenic proteins and druggable targets for sarcopenia through Mendelian randomization (MR)-based analytical framework. METHODS: A sequential stepwise screening method that includes two-sample MR, Steiger filtering test and colocalization (MRSC) was applied to identify causal proteins associated with sarcopenia-related traits. In the MR analyses, 4372 circulating proteins with valid instrumental variables (IVs) from eight proteomic genome-wide association studies were utilized as exposures, and nine sarcopenia-related traits were utilized as outcomes. IVs were classified into cis-protein quantitative trait loci (pQTLs) and trans-pQTLs based on their positions. We conducted cis-only MRSC analyses and cis + trans MRSC analyses using cis-pQTLs and cis + trans pQTLs as IVs, respectively. Post-MRSC analyses were conducted on the prioritized findings of MRSC, including annotation of protein-altering variants (PAVs), assessment of overlap between pQTLs and expression quantitative trait loci (eQTLs), protein-protein interaction (PPI) analysis, pathway enrichment analysis and annotation of drug targets. Utilizing data from the UK Biobank, we performed an observational study to explore the associations between baseline circulating protein levels and the longitudinal changes in nine sarcopenia-related traits. RESULTS: A total of 181 causal associations for 65 proteins were prioritized by the cis-only MRSC analyses and 227 associations for 91 proteins were prioritized by the cis + trans MRSC analyses. Among the prioritized proteins, the majority of them employed non-PAVs as IVs and most of their cis-pQTLs overlapped with corresponding eQTLs and exhibited consistent directionality, with only one trans-pQTL overlapping with an eQTL. The PPI network of cis-only MRSC-prioritized proteins (p = 4.04 × 10-4) and cis + trans MRSC-prioritized proteins (p = 8.76 × 10-5) showed significantly more interactions than expected. Reactome, KEGG and GO pathway enrichment analyses for cis-only MRSC-prioritized proteins identified 52, 12 and 79 enriched pathways, respectively (adjusted p < 0.05). For proteins identified by cis + trans MRSC analyses, only 15 pathways were enriched through the GO pathway enrichment analyses. In the observational study, 197 circulating proteins were identified to be associated with one or more sarcopenia-related traits (p < 0.05/2923). Among them, the significant associations of CTSB (negative association) and ASGR1 (positive association) with sarcopenia-related traits were observed to have consistent directional associations in both MR-based studies and observational studies. Drug target annotations suggested that 52 MRSC-prioritized proteins and 145 biomarkers are drug targets or druggable. CONCLUSIONS: This study identified 89 potential pathogenic proteins and 197 candidate biomarkers for sarcopenia, providing valuable clues for the development of therapeutic drugs for sarcopenia.

Humans↗

PubMed2025

PathwayVote: an R package for robust pathway enrichment analysis for DNA methylation data using a consensus-based voting framework.

MOTIVATION: Pathway enrichment analysis is commonly used to interpret epigenomewide association studies, yet conventional methods often rely on arbitrary thresholds and simplified CpG-gene mappings, making them sensitive to analytical choices and unable to fully leverage CpG-gene relationships Recent advances in expression quantitative trait methylation (eQTM) studies offer a rich resource to refine these mappings, but are rarely utilized in DNA methylation enrichment pipelines. RESULTS: We developed PathwayVote, an R package that implements a voting-based consensus approach and leverages eQTM data to identify robustly enriched pathways. PathwayVote reduces dependence on arbitrary cutoffs and improves sensitivity and reproducibility of enrichment results. AVAILABILITY AND IMPLEMENTATION: PathwayVote is freely available on GitHub (https://github.com/YinanZheng/PathwayVote) under the GPL-3 license and CRAN: https://CRAN.R-project.org/package=PathwayVote. The version of the code corresponding to this manuscript has been archived on Zenodo (https://doi.org/10.5281/zenodo.17209507).

Humans↗

PubMed1992

The folding of hen lysozyme involves partially structured intermediates and multiple pathways.

Analysis of the folding of hen lysozyme shows that the protein does not become organized in a single cooperative event but that different parts of the structure become stabilized with very different kinetics. In particular, in most molecules the alpha-helical domain folds faster than the beta-sheet domain. Furthermore, different populations of molecules fold by kinetically distinct pathways. Thus, folding is not a simple sequential assembly process but involves parallel alternative pathways, some of which may involve substantial reorganization steps.

Amino Acid Sequence↗

PubMed2026

Untargeted metabolomics reveals differential metabolic pathways and biomarkers in the acute phase of Kawasaki disease.

INTRODUCTION: Kawasaki disease (KD) is one of the most common rheumatic diseases in children and manifests with multisystem clinical features. Using untargeted metabolomics, our study investigated alterations in small-molecule metabolites in plasma of children with acute KD. Our study aimed to identify differential metabolic pathways and potential biomarkers. METHODS: Plasma samples were collected from 30 children diagnosed with KD and 30 age-matched healthy controls (HC) at Jinhua Maternal and Child Health Hospital between January 2025 and December 2025. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to analyse plasma samples. Enriched pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and differential metabolic pathways were determined using MetaboAnalyst 5.0. Differential metabolites were screened using the nonparametric Mann-Whitney U-test and receiver operating characteristic curve area (AUC). The conservative average AUC from nested cross-validation was reported as the primary performance metric. Pearson correlation analysis was conducted to evaluate correlations between metabolites and clinical parameters. RESULTS: In total, 261 differential metabolites were identified between the KD and HC groups, including 87 lipids and lipid-like molecules, 69 organic heterocyclic compounds, 38 benzenoids, 34 organic acids, 14 phenylpropanoids, and 19 other compounds. Pathway analysis of these differential metabolites revealed 30 putatively enriched metabolic pathways for exploratory analysis. Of these pathways, primary bile acid biosynthesis, arginine biosynthesis, histidine metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis were nominally associated with KD. Six metabolites with exploratory discriminatory performance (AUC > 0.8) were further identified: L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid. A combined model incorporating these metabolites achieved an apparent AUC of 0.984 in the full dataset; nested cross-validation yielded a more conservative AUC of 0.889 (95% CI 0.798-0.968), indicating promising exploratory discriminatory performance. CONCLUSION: Untargeted metabolomics enables identification of metabolically perturbed pathways during the acute phase of KD. L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid may serve as candidate biomarkers for acute phase of KD.

Kawasaki disease↗

PubMed2025

Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.

BACKGROUND: The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive. METHODS: Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters. RESULTS: Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy. CONCLUSION: We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.

Humans↗

PubMed2025

Acute Changes in Rat Tissue Gene Expression Following Exposure to Flight Relevant Hypobaria.

Aeromedical evacuation (AE) is an invaluable tool for the transport of critically injured patients to care facilities. There is increasing evidence obtained from animal models and human patients that exposure to AE-relevant hypobaria within a few days of injury can worsen outcomes. The cause of this secondary injury is not well understood but it may be related to changes in gene expression induced by exposure to evacuation-relevant conditions. In order to explore the causes of secondary injury, gene expression induced by AE-relevant flight conditions was analyzed. Adult male rats were exposed to flight cabin-relevant hypobaria (8000 or 4000 ft equivalents) and/or different oxygen concentrations (21% or 100%) for 5 or 10 hr. At the end of the exposures, RNA was isolated from lung, blood, heart, and brain (hippocampus), levels of gene expression were measured via microarray analysis, and canonical pathway analysis identified the primary gene pathways enriched by the exposures. This information should be useful to not only optimize the health status of trauma patients undergoing aeromedical evacuation but also help determine which gene expression pathways could be modulated to optimize the therapeutic efficacy of the body's endogenous protection and repair mechanisms.

Animals↗

PubMed2004

Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.

The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function.

Animals↗