Cellular inhibitor of apoptosis protein-1 (cIAP1) can regulate E2F1 transcription factor-mediated control of cyclin transcription.

The inhibitor of apoptosis protein cIAP1 (cellular inhibitor of apoptosis protein-1) is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-κB signaling pathways in the cytoplasm. However, in some primary cells and tumor cell lines, cIAP1 is expressed in the nucleus, and its nuclear function remains poorly understood. Here, we show that the N-terminal part of cIAP1 directly interacts with the DNA binding domain of the E2F1 transcription factor. cIAP1 dramatically increases the transcriptional activity of E2F1 on synthetic and CCNE promoters. This function is not conserved for cIAP2 and XIAP, which are cytoplasmic proteins. Chromatin immunoprecipitation experiments demonstrate that cIAP1 is recruited on E2F binding sites of the CCNE and CCNA promoters in a cell cycle- and differentiation-dependent manner. cIAP1 silencing inhibits E2F1 DNA binding and E2F1-mediated transcriptional activation of the CCNE gene. In cells that express a nuclear cIAP1 such as HeLa, THP1 cells and primary human mammary epithelial cells, down-regulation of cIAP1 inhibits cyclin E and A expression and cell proliferation. We conclude that one of the functions of cIAP1 when localized in the nucleus is to regulate E2F1 transcriptional activity.

cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand.

Peripheral blood monocytes are plastic cells that migrate to tissues and differentiate into various cell types, including macrophages, dendritic cells, and osteoclasts. We have described the migration of cellular inhibitor of apoptosis protein 1 (cIAP1), a member of the IAP family of proteins, from the nucleus to the Golgi apparatus in monocytes undergoing differentiation into macrophages. Here we show that, once in the cytoplasm, cIAP1 is involved in the degradation of the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) by the proteosomal machinery. Inhibition of cIAP1 prevents the decrease in TRAF2 expression that characterizes macrophage formation. We demonstrate that TRAF2 is initially required for macrophage differentiation as its silencing prevents Ikappa-Balpha degradation, nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation, and the differentiation process. Then, we show that cIAP1-mediated degradation of TRAF2 allows the differentiation process to progress. This degradation is required for the macrophages to be fully functional as TRAF2 overexpression in differentiated cells decreases the c-Jun N-terminal kinase-mediated synthesis and the secretion of proinflammatory cytokines, such as interleukin-8 and monocyte chemoattractant protein 1 (MCP-1) in response to CD40 ligand. We conclude that TRAF2 expression and subsequent degradation are required for the differentiation of monocytes into fully functional macrophages.

IAPs: more than just inhibitors of apoptosis proteins.

Inhibitors of apoptosis proteins (IAPs) are a conserved family of proteins identified in species ranging from virus, yeasts, nematodes, fishes, flies and mammals. The common structural feature is the presence of at least one Baculovirus IAP Repeat (BIR) domain. Hence, IAPs are also known as BIR-containing proteins (BIRCs). Most of them display anti-apoptotic properties when overexpressed. In drosophila, IAPs are sufficient and necessary to promote cell survival through a direct regulation of apoptotic proteases called caspases. In mammals, BIRC4/XIAP, the most studied IAP member can directly inhibit the activity of caspase-3, 7 and 9. However, this activity is not conserved in other IAPs and physiological relevancies of such anti-caspase activities are still discussed. A detailed analysis of IAP-deficient mice or derived cells, deletion experiments performed in drosophila and zebrafish, or research of protein partners have revealed the importance of IAPs in adaptive response to cellular stress, in cell proliferation, differentiation, signaling, motility and in immune response. This review discusses recent data that help understanding of cellular functions of IAPs.