BRCA1 185delAG Mutation Enhances Interleukin-1𝛽 Expression in Ovarian Surface Epithelial Cells

Woolery, Kamisha T.; Mohamed, Mai; Linger, Rebecca J.; Dobrinski, Kimberly P.; Roman, Jesse; Kruk, Patricia A.

BRCA1 185delAG Mutation Enhances Interleukin-1𝛽 Expression in Ovarian Surface Epithelial Cells

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Dobrinkski_BRCA1 185delAG Mutation Enhances Interleukin-1 Expression_Final.pdf (1.96 MB)

Date

2015-06-17

Authors

Woolery, Kamisha T.

Mohamed, Mai

Linger, Rebecca J.

Dobrinski, Kimberly P.

Roman, Jesse

Kruk, Patricia A.

Publisher

BioMed Research International, Hindawi Publishing Corporation

Abstract

Familial history remains the strongest risk factor for developing ovarian cancer (OC) and is associated with germline BRCA1 mutations, such as the 185delAG founder mutation. We sought to determine whether normal human ovarian surface epithelial (OSE) cells expressing the BRCA1 185delAG mutant, BRAT, could promote an inflammatory phenotype by investigating its impact on expression of the proinflammatory cytokine, Interleukin-1𝛽 (IL-1𝛽). Cultured OSE cells with and without BRAT were analyzed for differential target gene expression by real-time PCR, western blot, ELISA, luciferase reporter, and siRNA assays.We found that BRAT cells expressed increased cellular and secreted levels of active IL-1𝛽. BRAT-expressing OSE cells exhibited 3-fold enhanced IL- 1𝛽 mRNA expression, transcriptionally regulated, in part, through CREB sites within the (−1800) to (−900) region of its promoter. In addition to transcriptional regulation, BRAT-mediated IL-1𝛽 expression appears dualistic through enhanced inflammasomemediated caspase-1 cleavage and activation of IL-1𝛽. Further investigation is warranted to elucidate the molecularmechanism(s) of BRAT-mediated IL-1𝛽 expression since increased IL-1𝛽 expression may represent an early step contributing to OC.

Description

Copyright © 2015 Kamisha T. Woolery et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Final Published Version

Keywords

Ovarian cancer, BRCA genes, Epithelial cells, Interleukin-1, Gene Expression Regulation, Cytokines, Inflammasomes

Citation

Woolery KT, Mohamed M, Linger RJ, Dobrinski KP, Roman J, Kruk PA. BRCA1 185delAG Mutation Enhances Interleukin-1β Expression in Ovarian Surface Epithelial Cells. Biomed Res Int. 2015;2015:652017. doi:10.1155/2015/652017