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| Status |
Public on Sep 08, 2016 |
| Title |
Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| 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.
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| Contributor(s) |
Gupta R, Forloni M, Dogra S, Bisserier M, Yang Q, Wajapeyee N |
| Citation(s) |
27608486 |
| Submission date |
Oct 29, 2014 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Narendra Wajapeyee |
| E-mail(s) |
nwajapey@uab.edu
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| Phone |
205-934-5331
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| Organization name |
University of Alabama at Birmingham
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| Department |
Department of Biochemistry and Molecular Genetics
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| Street address |
720 20th Street South, Kaul 540A
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35233 |
| Country |
USA |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA265380 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE62827_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE62827_non-normalized.txt.gz |
3.4 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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