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FAM83B mediates EGFR- and RAS-driven oncogenic transformation
Rocky Cipriano, … , George R. Stark, Mark W. Jackson
Rocky Cipriano, … , George R. Stark, Mark W. Jackson
Published August 13, 2012
Citation Information: J Clin Invest. 2012;122(9):3197-3210. https://doi.org/10.1172/JCI60517.
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Research Article Article has an altmetric score of 3

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

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Abstract

Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention.

Authors

Rocky Cipriano, James Graham, Kristy L.S. Miskimen, Benjamin L. Bryson, Ronald C. Bruntz, Sarah A. Scott, H. Alex Brown, George R. Stark, Mark W. Jackson

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Figure 7

FAM83B-mediated transformation requires CRAF and mTOR signaling.

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FAM83B-mediated transformation requires CRAF and mTOR signaling.
(A and ...
(A and B) FAM83B-expressing HME1 cells were treated with U0126 (1.5 μM), rapamycin (11 nM), or RAF kinase inhibitor I (100 and 600 nM) and assessed for AIG. (C and D) HME1 cells expressing FAM83B were infected with lentiviruses encoding shRNA targeting GFP or CRAF and assessed for growth and AIG. (E) MCF7 and MDA468 cells expressing shRNA targeting GFP, CRAF, or FAM83B were assessed for growth. (F) MDA468 cells expressing shRNA targeting GFP, CRAF, or FAM83B were assessed for AIG. (G) 293T cells were transfected with expression constructs encoding CRAF, GFP, and FAM83B, and immuno­precipitation was performed. Immunoprecipitation was also performed on lysates from HME1 cells stably expressing GFP or FAM83B. (H) 293T cells were transfected with expression constructs encoding CRAF, GFP, full-length FAM83B, FAM83B-482, and FAM83B-ΔDUF1669, and immuno­precipitation was performed. (I) Immunoprecipitation was performed on lysates from HME1 cells stably expressing GFP or FAM83B. (J) Cytoplasmic (C) and membrane (M) fractions from HME1 cells expressing GFP or FAM83B were analyzed by Western blotting. (K) Immuno­precipitation was performed on lysates from MDA468 cells expressing shRNA targeting GFP or FAM83B. (L) Immuno­fluorescence using confocal microscopy was performed in 293T cells transfected with GFP or FAM83B. Original magnification, ×63. (M) Whole cell extract (WCE), cytoplasmic (C), membrane (M), nuclear (N), and chromatin-bound (CB) fractions from 293T cells expressing GFP or FAM83B were analyzed by Western blotting. All experiments were performed in triplicate, and mean ± SD are shown. Lanes in I were run on the same gel but were noncontiguous (white lines).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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