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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 29, 2011 |
| Title |
Autocrine IL-1α mediates NF-κB activation by oncogenic ras in keratinocytes |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Constitutively active RAS plays a central role in the development of skin cancer in the classical two stage skin carcinogenesis in mice and in a number of human cancers. Ras-mediated tumor formation is commonly associated with upregulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. MyD88 is a crucial intermediate in the expression of multiple innate immune responders through signaling from the Toll-like/IL-1R family. We report that mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis, and cultured MyD88-/- keratinocytes transduced with an oncogenic ras vector form only a few small tumors in orthotopic grafts. Initiated keratinocytes arising from oncogenic activation of ras are hyperproliferative but also resist signals for induced differentiation and upregulate a host of pro-inflammatory genes. Ras-transduced MyD88-/- keratinocytes are also hyperproliferative but the differentiation response is intact and pro-inflammatory genes are not upregulated. Using both genetic and pharmacological approaches, we find that in keratinocytes, the differentiation and immune regulation functions mediated by oncogenic ras require the establishment of an autocrine loop through IL-1α and its receptor leading to NF-κB activation. In the absence of MyD88 or IL-1R, this loop cannot be established. Further, blocking the IL-1a mediated NF-κB activation in ras-transduced wildtype keratinocytes corrects the defect in both differentiation response and proinflammatory gene expression. Collectively, these results demonstrate that ras activation converts normal keratinocytes to an initiated phenotype through a series of potentially reversible feedback signals that provide therapeutic opportunities through inhibition of IL-1 signaling.
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| Overall design |
Gene expression comparison of wild type ras-transformed keratinocytes untreated (n=3) or treated (n=3) in vitro with the IL1R antagonist Anakinra.
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| Contributor(s) |
Cataisson C, Salcedo R, Shakeeb H, Barrett A, Yi M, Ren-Ming D, Lyakh L, Yuspa SH, Stephens RM, Trinchieri G |
| Citation(s) |
22908325 |
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| Submission date |
Jul 06, 2010 |
| Last update date |
May 10, 2018 |
| Contact name |
Rosalba Salcedo |
| E-mail(s) |
lmirosi@mail.ncifcrf.gov
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| Phone |
301-846-6274
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| Fax |
301-846-6641
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| Organization name |
SAIC-NCI
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| Street address |
1050 Boyles Street, Bldg. 567
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| City |
Frederick |
| State/province |
MD |
| ZIP/Postal code |
21701 |
| Country |
USA |
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| Platforms (1) |
| GPL4134 |
Agilent-014868 Whole Mouse Genome Microarray 4x44K G4122F (Feature Number version) |
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| Samples (6)
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| GSM575312 |
v-ras-Ha transformed keratinocytes without IL1ra, rep1 |
| GSM575313 |
v-ras-Ha transformed keratinocytes without IL1ra, rep2 |
| GSM575314 |
v-ras-Ha transformed keratinocytes without IL1ra, rep3 |
| GSM575315 |
v-ras-Ha transformed keratinocytes with IL1ra, rep1 |
| GSM575316 |
v-ras-Ha transformed keratinocytes with IL1ra, rep2 |
| GSM575317 |
v-ras-Ha transformed keratinocytes with IL1ra, rep3 |
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| Relations |
| BioProject |
PRJNA128083 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE22777_RAW.tar |
54.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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