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Title: Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformation      
keywords:
Transcriptome or Gene expression
ID:
PRJNA265380
description:
Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma. Overall design: MEL-ST cells expressing either empty vector or mutant oncogenic RAS genes (HRAS v12, KRAS v12, NRAS Q61K) were used to isolate total RNA. The RNA was then used to perform gene expression analyses using the Illumina HumanHT-12 V4.0 Expression BeadChip array.
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA265380
authentication:
none
authorization:
none
ID:
pmid:27608486
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • R01 CA200919/CA/NCI NIH HHS/United States

  • UL1 TR001863/TR/NCATS NIH HHS/United States

  • R21 CA191364/CA/NCI NIH HHS/United States

  • P30 CA016359/CA/NCI NIH HHS/United States

  • R21 CA197758/CA/NCI NIH HHS/United States

  • R21 CA195077/CA/NCI NIH HHS/United States

  • R01 CA196566/CA/NCI NIH HHS/United States

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