Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA234087 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1105810.fastq.gz | Fastqsanger.gz | |||
| SRR1105820.fastq.gz | Fastqsanger.gz | |||
| SRR1105811.fastq.gz | Fastqsanger.gz | |||
| SRR1105802.fastq.gz | Fastqsanger.gz | |||
| SRR1105812.fastq.gz | Fastqsanger.gz |
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Project description:Frequent mutations in human breast cancer tumors detected with Ion Torrent Ampliseq Cancer Panel
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Project description:Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but also recurrent in epithelial malignancies such as breast cancer. Whereas hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3’ splice sites induced by mutant SF3B1, a portion of which were breast-specific. Across mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the aberrant branchpoint) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify mutations in SF3B1 as drivers of breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.
2021-01-05 | GSE145471 | GEO
Project description:Tumor genomic profiling has uncovered many cancer drivers whose implications in terms of tumor biology and therapeutic actionability remain understudied. Hotspot mutations in SF3B1 induce widespread transcriptomic alterations and occur across multiple cancer types. Despite this, the biological and clinical consequences of SF3B1 mutations remain elusive. Characterization of the largest SF3B1 mutant breast cancer clinical cohort to date identifies SF3B1 driver mutations in approximately 2.5% of HR+ HER2- breast cancer, with strong enrichment of K700E substitutions, substantial variation in variant allele fraction, and significantly improved overall survival. In-vitro and in-vivo studies in representative cell models suggest several of the most prevalent SF3B1 mutations have deleterious effects on cell growth, leading to selective loss of the mutation over time, providing a rationale for the low frequency and low VAF of SF3B1 mutations in breast cancer. Though all introduced hotspot mutations limit growth and are reverted to wildtype over time, mutations at position R625 have a more pronounced phenotype than K700E, providing an explanation for the clinically observed skew in mutation frequencies. RNA and DNA sequencing analyses were used to identify characteristic pathway-level transcriptomic changes in SF3B1-mutant cells and identify copy number alterations as a mechanism of both improved mutation tolerability and a means to eliminate the mutation over time. These data suggest that while SF3B1 mutations are enriched in some clinical contexts, their role in breast tumorigenesis is highly complex and dependent on secondary events that overcome their deleterious effects on cell growth and survival.
2025-09-30 | GSE304350 | GEO
Project description:Gene expression influenced by SF3B1 inhibitor, FR901464 or SF3B1 gene mutations in colorectal cancer cells
| PRJNA251682 | ENA
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature
Project description:PurposeWe investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level.MethodsSNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively.ResultsSix of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes.ConclusionsThere is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.
| S-EPMC3743458 | biostudies-literature