Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41002 (CCNF)
 32 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neratinib (HKI-272) is a small molecule tyrosine kinase inhibitor of the ErbB receptor family currently in Phase III clinical trials. Despite its efficacy, the mechanism of potential cellular resistance to neratinib and genes involved with it remains unknown. We have used a pool-based lentiviral genome-wide functional RNAi screen combined with a lethal dose of neratinib to discover chemoresistant interactions with neratinib. Our screen has identified a collection of genes whose inhibition by RNAi led to neratinib resistance including genes involved in oncogenesis (e.g. RAB33A, RAB6A and BCL2L14), transcription factors (e.g. FOXP4, TFEC, ZNF), cellular ion transport (e.g. CLIC3, TRAPPC2P1, P2RX2), protein ubiquitination (e.g. UBL5), cell cycle (e.g. CCNF), and genes known to interact with breast cancer-associated genes (e.g. CCNF, FOXP4, TFEC, several ZNF factors, GNA13, IGFBP1, PMEPA1, SOX5, RAB33A, RAB6A, FXR1, DDO, TFEC, OLFM2). The identification of novel mediators of cellular resistance to neratinib could lead to the identification of new or neoadjuvant drug targets. Their use as patient or treatment selection biomarkers could make the application of anti-ErbB therapeutics more clinically effective.
Mol Biosyst 2012 Apr
PMID:A genome-wide RNAi screen identifies novel targets of neratinib resistance leading to identification of potential drug resistant genetic markers. 2244 32

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the death of upper and lower motor neurons. Approximately 10% of cases have a known family history of ALS and disease-linked mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible disease mechanisms, we developed in vitro and in vivo models based on an ALS-linked missense mutation in CCNF. Proteomic analysis of the in vitro models identified the disruption of several cellular pathways in the mutant model, including caspase-3 mediated cell death. Transient overexpression of human CCNF in zebrafish embryos supported this finding, with fish expressing the mutant protein found to have increased levels of cleaved (activated) caspase-3 and increased cell death in the spinal cord. The mutant CCNF fish also developed a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. Importantly, we demonstrated a significant correlation between the severity of the CCNF-induced axonopathy and a reduced motor response to a light stimulus (photomotor response). This is the first report of an ALS-linked CCNF mutation in vivo and taken together with the in vitro model identifies the disruption of cell death pathways as a significant consequence of this mutation. Additionally, this study presents a valuable new tool for use in ongoing studies investigating the pathobiology of ALS-linked CCNF mutations.
Hum Mol Genet 2017 07 15
PMID:Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype. 3037 81

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin-proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal-lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis.
Cell Mol Life Sci 2018 01
PMID:Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy. 2885 78

Kidney renal cell carcinoma (KIRC), which is the most common subtype of kidney cancer, has a poor prognosis and a high mortality rate. In this study, a multi-omics analysis is performed to build a multi-gene prognosis signature for KIRC. A combination of a DNA methylation analysis and a gene expression data analysis revealed 863 methylated differentially expressed genes (MDEGs). Seven MDEGs (BID, CCNF, DLX4, FAM72D, PYCR1, RUNX1, and TRIP13) were further screened using LASSO Cox regression and integrated into a prognostic risk score model. Then, KIRC patients were divided into high- and low-risk groups. A univariate cox regression analysis revealed a significant association between the high-risk group and a poor prognosis. The time-dependent receiver operating characteristic (ROC) curve shows that the risk group performs well in predicting overall survival. Furthermore, the risk group is contained in the best multivariate model that was obtained by a multivariate stepwise analysis, which further confirms that the risk group can be used as a potential prognostic biomarker. In addition, a nomogram was established for the best multivariate model and shown to perform well in predicting the survival of KIRC patients. In summary, a seven-MDEG signature is a powerful prognosis factor for KIRC patients and may provide useful suggestions for their personalized therapy.
Int J Mol Sci 2019 Nov 14
PMID:A Gene Signature of Survival Prediction for Kidney Renal Cell Carcinoma by Multi-Omic Data Analysis. 3173 30

Ankylosing spondylitis (AS) is a chronic rheumatic disease that mainly affects the spinal joints (vertebrae). Spondylitis means inflammation of the spine, and ankylosing spondylitis means that bones tend to fuse. The AS causes the vertebrae to swell in the spine. Therefore, based on protein interaction network analysis, we conducted in-depth research on the molecular mechanism of key regulatory factors in the AS disease process. We carried out a differential analysis of the expression of miRNAs in disease samples and miRNAs in normal samples. Protein network interaction analysis is performed according to a group of target genes regulated by significant differentially expressed miRNAs and clustered into an interaction module. In addition, enrichment analysis of functions and pathways was performed on these modular genes. Based on the predictive analysis of multidimensional regulators, we identified a range of regulatory factors that have potential regulatory effects on AS, such as endogenous genes and transcription factors. We obtained 20 differentially expressed miRNAs and 7082 target genes and clustered into 11 modules. Enrichment results showed that these modular genes are mainly involved in the functions and pathways of protein polyubiquitination, neutrophil activation involved in immune response, and Wnt signaling pathway. We revealed ten transcription factors (MYC, NFKB1, and TP53). After network connectivity analysis, we obtained 12 internal drive genes (UBE2D1, CCNF, and NEDD4). These core genes are thought to be potential regulators of AS. MYC is also considered to be a core factor that inhibits SART3 phosphorylation and plays a vital role in the immunological pathogenesis of AS. The combination of the above analysis results can provide a new idea for biologists and medical scientists to study the immune pathogenesis of AS and can provide a valuable reference for subsequent treatment options.
Cell Mol Biol (Noisy-le-grand) 2020 Jul 31
PMID:Potential regulatory factors in the pathogenesis of ankylosing spondylitis. 3304 Aug 22