The penetrant chordoid glioma PRKCA mutation is an oncogenic gain-of-function kinase inactivation eliciting early onset chondrosarcoma in mice
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ABSTRACT:
PROVIDER: PRJNA1122210 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29351100.fastq.gz | Fastqsanger.gz | |||
| SRR29351101.fastq.gz | Fastqsanger.gz | |||
| SRR29351102.fastq.gz | Fastqsanger.gz | |||
| SRR29351103.fastq.gz | Fastqsanger.gz | |||
| SRR29351104.fastq.gz | Fastqsanger.gz |
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Project description:A highly penetrant heterozygous mutation in PRKCA was found recently in chordoid glioma. To establish whether this mutant of PKCapha was a driver of tumour formation or maintenance in vivo, knock-in mice were generated. The constitutive, heterozygous expression of the Prkca D463H mutant in mice provoked the development of bilateral hindlimb chondrosarcomas and early neonatal mortality. The lack of activity of the D463H mutant was not the trigger of the phenotype as heterozygous knock-in of the related inactivating mutation D463N produced offspring indistinguishable from parental strains. Moreover, this surprising distinction between D463H and D463N mutations did not reflect a selective lack of dominance for the D463N mutation over the wild type (WT) allele since homozygous expression of this mutation was phenotypically WT. In cell culture, the D463H mutant expression, localisation and downregulation behaviours closely mimicked that of the WT, with the D463N mutant displaying some subtle differences. Biochemically, both the D463H and D463N mutants were shown to be inactive, although based on thermal shift assays the D463N mutant had reduced ATP affinity compared to WT or D463H proteins. Using induced transcriptional changes as a functional readout, altered mRNA expression indicates that the D463H acts as a dominant gain-of-function PKC mutant, despite a complete lack of intrinsic kinase activity; transcriptional changes induced by the D463N mutant were distinct from both the WT and D463H mutant. These findings suggest a model in which there is a non-catalytic effector function of PKCalpha which it is presumed operates through protein-protein interactions, as evidenced here by TurboID proximity labelling. The penetrant selection of the specific inactivating D463H mutation in chordoid glioma and the distinction with the D463N mutation indicates that this is conformationally sensitive. The properties characterised suggest this is driven by ATP binding and by inference, in this tissue context, the catalytic activity of this kinase acts as an autoregulatory negative feedback control.
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Project description:These libraries represent instances of Swarm rat chondrosarcoma tumors taken from different transplantation experiments. This series also contains one non-cancerous cartilage library made from rat normal growing femoral head cartilage as a comparative data point. Keywords: other
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Project description:Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting ROS accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated SLC1A5 and GLS expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
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