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Interaction Between FAM129B, a Novel Adherent Junction protein, and KELCH‐like Associated Protein 1 (KEAP1) suppresses Apoptosis in Cancer Cells.
Author(s) -
Hachem Fatme Ali,
Chen Song Ali,
Evans Hedeel Guy,
Evans David R.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.774.8
Subject(s) - apoptosis , cancer cell , iκb kinase , microbiology and biotechnology , gene silencing , biology , programmed cell death , signal transduction , chemistry , cancer research , cancer , nf κb , genetics , gene
FAM129B, is a member of a family of novel proteins that include FAM129A and FAM129C. Little is known about the structure and functions of these proteins Preliminary data in our lab suggests that FAM129B plays a role in apoptosis suppression and promotes cancer cell invasion. Suppression of apoptosis is one of the mechanisms used by cancer cells to evade cell death and facilitate metastatic spread. FAM129B expression is highly elevated in cancer cell lines compared to non‐cancer cell lines as suggested by western blot analysis. Here, we have shown that FAM129B exclusively suppresses the TNFα induced apoptotic pathway and not the Fas‐mediated apoptosis and the mitochondrial pathway in cancer cells. We then investigated the effect of FAM129B on several components of the TNFα pathway: IkB kinase (IKKβ), the transcription factor NF‐kB, and the anti‐apoptotic proteins c‐FLIP, and cIAP. Silencing FAM129B expression using siRNA in can cells promoted IKKβ degradation and decreased NF‐kB translocation to the nucleus and the expression of c‐FLIP and cIAP following induction of apoptosis. We also show that KEAP1, a protein that promotes IKKβ degradation, forms a complex with FAM129B in vivo and in vitro . The ETGE motif in FAM129B and the KELCH repeats in KEAP1 are the sites of interaction between the two proteins. Using site directed mutagenesis, we changed the ETGE motif into ETAA. This mutation disrupted the interaction with KEAP1. Overexpression of recombinant FAM129B with the mutated ETGE motif in cancer cells, in contrast to the wild type protein, did not suppress apoptosis . We propose that FAM‐129B sequesters KEAP‐1, and blocks apoptosis by promoting the NF‐κB signaling pathway and the expression of antiapoptotic proteins