Role of APIM in the NF-κB signaling network

Abstract

Decades of research have revealed that the nuclear factor-κB (NF-κB) is an important functional transcription factor which lately is also found to be constitutively active in many cancer cells such as multiple myeloma cell lines (Annunziata, Davis et al. 2007; Demchenko, Glebov et al. 2010). The APIM-sequence, which was recently identified as a functional PCNA-interacting motif, is found in more than 200 proteins important in DNA maintenance, transcription and cell cycle regulation (Gilljam, Feyzi et al. 2009). Some of the APIM-containing proteins are suggested to act upstream of the NF-κB pathway. Overexpression of the APIM-peptide makes cells more sensitive to DNA-damaging agents likely by blocking the binding between PCNA and DNA repair/cell cycle regulatory proteins containing the APIM sequence, thereby impairing the proper cellular response to damage. We have investigated APIM-peptide's effect on NF-κB activity after exposure to lipopolysaccharides (LPS) and various DNA-damaging agents. LPS stimulation of monocytes activates NF-κB, which leads to tumor necrosis factor-alpha (TNF-α) production, which again activates NF-κB. Immunoassay demonstrated a significant decreased in production of TNF-α form in freshly isolated monocytes treated with LPS in the presence of the APIM-peptide. We suggest that the APIM-peptide is a promising inhibitor of TNF-α and possibly NF-κB activity, and that APIM-containing proteins such as MAPKs, MASTs and PI3Ks acting upstream of NF-κB signaling might be involved.