REQUIREMENT FOR PKC EPSILON IN KRAS-DRIVEN LUNG TUMORIGENESIS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA627658 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11596765.fastq.gz | Fastqsanger.gz | |||
| SRR11596766.fastq.gz | Fastqsanger.gz | |||
| SRR11596767.fastq.gz | Fastqsanger.gz | |||
| SRR11596768.fastq.gz | Fastqsanger.gz | |||
| SRR11596769.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 18 |
Similar Datasets
Project description:Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCe, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCe expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCe-deficient, conditionally activatable allele of oncogenic Kras (LSL-Kras G12D ;PKCe -/- mice) we were able to demonstrate the requirement of PKCe for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCe-deficient KRAS-dependent NSCLC cells. Moreover, PKCe-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCe and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCe in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCe for lung cancer therapeutics.
2020-07-31 | GSE149205 | GEO
Project description:Atrial fibrillation (AF), the most common abnormal heart rhythm, is a major cause for stroke. Aging is the greatest risk factor for AF, however, specific ionic pathways that can elucidate how aging leads to AF remain elusive. We used young and old wild type (WT) and PKC epsilon (PKCepsilon) knockout (KO) mice, whole animal, and cellular electrophysiology, as well as whole heart, and cellular imaging to investigate how aging leads to the aberrant functioning of a potassium current, and consequently to AF facilitation. Our experiments showed that knocking out PKC epsilon abrogates the effects of aging on AF by preventing the development of a constitutively active acetylcholine sensitive inward rectifier potassium current (IKACh). Moreover, blocking this abnormal current in the old heart prevents AF inducibility. Our studies demonstrate that in the aging heart, IKACh is constitutively active in a PKC epsilon dependent manner, contributing to the perpetuation of AF
2022-10-07 | MSV000090489 | MassIVE
Project description:Non-small cell lung cancer (NSCLC) is the most frequent subtype of lung cancer and remains a highly lethal malignancy and one of the leading causes of cancer-related deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histologic form of NSCLC. In this study, we examined the role of PKCϵ, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Database analysis revealed an association between PKCϵ expression and poor outcome in patients with lung adenocarcinoma specifically harboring KRAS mutations. A PKCϵ-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D ;PKCϵ-/- mice) demonstrated the requirement of PKCϵ for Kras-driven lung tumorigenesis in vivo, which was consistent with impaired transformed growth reported in PKCϵ-deficient KRAS-dependent NSCLC cells. Moreover, PKCϵ-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA sequencing revealed little overlap for PKCϵ and KRAS in the control of genes and biological pathways relevant in NSCLC, suggesting that a permissive role of PKCϵ in KRAS-driven lung tumorigenesis may involve nonredundant mechanisms. Our results thus, highlight the relevance and potential of targeting PKCϵ for lung cancer therapeutics. SIGNIFICANCE: These findings demonstrate that KRAS-mediated tumorigenesis requires PKCϵ expression and highlight the potential for developing PKCϵ-targeted therapies for oncogenic RAS-driven malignancies.
| S-EPMC7962984 | biostudies-literature
Project description:Protein kinase C epsilon plays important roles in behavioral responses to alcohol and in anxiety-like behavior in rodents, making it a potential drug target for reducing alcohol consumption and anxiety. Identifying signals downstream of PKC Epsilon could reveal additional targets and strategies for interfering with PKC Epsilon signaling. We used a chemical genetic screen combined with mass spectrometry to identify direct substrates of PKC Epsilon, and validated findings for 43 of them using peptide arrays and in vitro kinase assays. Prioritizing substrates with several public databases such as LINCS-1000, STRING, GeneFriends, and GeneMAINA, predicted interactions between these putative substrates and PKC Epsilon, and identified substrates associated with alcohol-related behaviors, actions of benzodiazepines, and chronic stress. The 43 substrates could be broadly classified in three functional categories: cytoskeletal regulation, morphogenesis, and synaptic release. These results provide a list of brain PKC Epsilon substrates, many of which are novel, for future investigation to determine the role of PKC Epsilon signaling in alcohol responses, anxiety, responses to stress, and other related behaviors.
2022-06-15 | MSV000089659 | MassIVE
Project description:KRAS induces lung tumorigenesis through microRNAs modulation
| PRJNA433453 | ENA
Project description:KRAS mutation-selective requirement for ACSS2 in colorectal adenoma formation.
| PRJNA1086508 | ENA
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress
Project description:Oncogenic KRAS mutations are prevalent in colorectal cancer (CRC) and are associated with poor prognosis and resistance to therapy. There is a substantial diversity of KRAS mutant alleles observed in CRC. Emerging clinical and experimental analysis of common KRAS mutations suggest that each mutation differently influences the clinical properties of a disease and response to therapy. Although there is some evidence to suggest biological differences between mutant KRAS alleles, these are yet to be fully elucidated. One approach to study allelic variation involves the use of isogenic cell lines that express different endogenous Kras mutants. Here, we generated Kras isogenic Apc-/- mouse colon epithelial cell lines using CRISPR-driven genome editing by altering the original G12D Kras allele to G12V, G12R, or G13D. We utilized these cell lines to perform transcriptomic and proteomic analysis to compare different signaling properties between these mutants. Both screens indicate significant differences in pathways relating to cholesterol and lipid regulation that we validated with targeted metabolomic measurements and isotope tracing. We found that these processes are upregulated in G12V lines through increased expression of nuclear SREBP1 and higher activation of mTORC1. G12V cells showed higher expression of ACSS2 and ACSS2 inhibition sensitized G12V cells to MEK inhibition. Finally, we found that ACSS2 plays a crucial role early in the development of G12V mutant tumors, in contrast to G12D mutant tumors. These observations highlight differences between KRAS mutant cell lines in their signaling properties. Further exploration of these pathways may prove to be valuable for understanding how specific KRAS mutants function, and identification of novel therapeutic opportunities in CRC.
2025-05-02 | PXD050157 | Pride
Project description:The PKC-regulated genome protective pathway provides transformed cells a failsafe to successfully complete mitosis. Despite the necessary role for Aurora B in this programme, it is unclear whether its requirement is sufficient or if other PKC cell cycle targets are involved. To address this, we developed a trapping strategy using UV-photocrosslinkable amino acids encoded in the PKC kinase domain. The validation of the mRNA binding protein SERBP1 as a PKC substrate revealed a series of mitotic events controlled by the catalytic form of PKC. PKC represses protein translation, altering SERBP1 binding to the 40S ribosomal subunit and promoting the assembly of ribonucleoprotein granules containing SERBP1, termed M-bodies. Independent of Aurora B, SERBP1 is shown to be necessary for chromosome segregation and successful cell division, correlating with M-body formation. This requirement for SERBP1 demonstrates that Aurora B acts in concert with translational regulation in the PKC-controlled pathway exerting genome protection.
2021-12-09 | PXD029091 | Pride
Project description:KRAS, mutated in ~30% of all cancers, activates the RAF-MEK-ERK signaling cascade. It has previously been shown that CRAF is required for growth of KRAS mutant lung tumors but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescued growth inhibition suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrated enrichment of CRAF:ARAF dimers in KRAS mutant cells and depletion of both CRAF and ARAF rescued the CRAF loss phenotype. Mechanistically, CRAF depletion caused sustained ERK activation and induction of cell cycle arrest. Treatment with low dose MEK or ERK inhibitor rescued the CRAF loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting dimerization or degrading CRAF may have therapeutic benefit.
2021-10-29 | MSV000088285 | MassIVE