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

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

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 4

Inhibition of FAM83B suppresses the tumorigenicity and growth of cancer cells.

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Inhibition of FAM83B suppresses the tumorigenicity and growth of cancer ...
(A) Northern analysis of FAM83B expression in MDA468 cells. (B and C) Ablation of FAM83B by shRNA inhibited MDA468 AIG and acini formation in lrBM. Original magnification, ×10. (D and E) MDA468 cells were infected with shRNAs targeting GFP (G) or FAM83B (B2) and injected subcutaneously into immunocompromised mice to assess tumor formation; both tumor volume and tumor size are shown. (F) Ablation of FAM83B in ovarian, cervical, and lung cancer cell lines inhibited their growth. SKOV3, HeLa, and H1299 cancer cell lines and normal diploid BJ fibroblasts expressing hTERT (BJ-T) were infected with lentiviruses encoding shRNA targeting GFP or FAM83B, and cell number was assessed 8 days after plating. All experiments were performed in triplicate, and mean ± SD are shown.