Dominant negative form of signal-regulatory protein-α (SIRPα/SHPS-1) inhibits tumor necrosis factor-mediated apoptosis by activation of NF-κB

Abstract

Genetic suppressor element (GSE) methodology was applied to identify new genes controlling cell response to tumor necrosis factor (TNF). A retroviral library of randomly fragmented normalized cDNA from mouse fibroblasts was screened for GSEs capable of protecting NIH3T3 cells from TNF-induced apoptosis. The most abundant among isolated GSEs represented a fragment of cDNA encoding the C-terminal cytoplasmic region of the immunoglobulin family inhibitory receptor, SHPS-1 (mouse homologue of human SIRPα). Ectopic expression of this fragment (both from human and mouse versions) increased the NF-κB-dependent transcription in three cell lines tested; this effect could be reduced by the expression of full-length SIRPα, suggesting that the isolated GSE acts through a dominant negative mechanism. GSE-mediated activation of NF-κB depended on the presence of serum, was abrogated by wortmannin, and was associated with phosphorylation of PKB/Akt, suggesting that Akt mediates it. These data indicate that SIRPα/SHPS-1 is involved in negative regulation of NF-κB signaling.