Abstract

NF-kB plays an important role in the transcriptional regulation of a variety of genes involved in immune and inflammatory responses and cell survival. There has been increasing experimental evidence suggesting that abnormalities in the regulation of NF-kB activity are tightly linked to the pathogenesis of inflammatory disorders, neurodegenerative diseases as well as chronic inflammatory diseases. The transcriptional activation by NF-kB requires interactions with multiple cofactors. We earlier provided evidence that NF-kB interacts directly with Poly-(ADP-ribose) polymerase-1 (PARP-1) through both subunits of NF-kB p65 and p50, respectively. The enzymatic as well as the DNA binding activity of PARP-1 was not required for NF-kB-dependent gene expression. NF-kB has also been described to interact with the transcriptional coactivator p300. Interestingly, in PARP-1 knock out cells the recruitment of the transcriptional coactivator p300 by NF-kB was not sufficient for NF-kB-dependent gene expression. Functional complementation revealed that the C-terminal end of PARP-1 was required for transcriptional activity of NF-kB in response to TNF-a and LPS, but not PMA. Moreover, we will provide evidence that PARP-1 plays an essential regulatory role in NF-kB-dependent gene expression by enhancing synergistically with p300 the assembly of a transcriptional pre-initiation complex. References: 1.Hassa PO, Hottiger MO: A role of poly (ADP-ribose) polymerase in NF-kB transcriptional activation. Biol Chem, 1999; 380: 953-959 2.Hassa PO, Covic M, Hasan S, Imhof R, Hottiger MO: The Enzymatic and DNA binding Activity of PARP-1 Are Not Required for NF-kB Coactivator Function. J Biol Chem, 2001; 276(49): 45588-45597 3.Hassa PO, Hottiger MO: The Functional Role of Poly(ADP Ribose)Polymerase 1 (PARP-1) in Inflammatory Disorders. Cell Mol Life Sci, 2002; 59: 1534-1553

Keywords: PARP-1, NF-kB, p300, transcriptional coactivator