1. ¹Department of Veterans Affairs, Vanderbilt University School of Medicine, Nashville, TN, USA
2. ²Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
3. ³Department of Microbiology, Meharry Medical College, Nashville, TN, USA
4. ⁴Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC, USA

Correspondence: Professor A Richmond, Department of Cancer Biology, Vanderbilt University School of Medicine, 771 PRB, 23rd Ave. South at Pierce, Nashville, TN 37232, USA. E-mail: ann.richmond@vanderbilt.edu

Received 27 February 2006; Revised 11 May 2006; Accepted 11 May 2006; Published online 26 June 2006.

Abstract

The continuous production of the CXC ligand 1 (CXCL1) chemokine by melanoma cells is a major effector of tumor growth. We have previously shown that the constitutive expression of this chemokine is dependent upon transcription factors nuclear factor-kappa B (NF-B), stimulating protein-1 (SP1), high-mobility group-I/Y (HMGI/Y), CAAT displacement protein (CDP) and poly(ADP-ribose) polymerase-1 (PARP-1). In this study, we demonstrate for the first time the mechanism of transcriptional regulation of CXCL1 through PARP-1 in melanoma cells. In its inactive state, PARP-1 binds to the CXCL1 promoter in a sequence-specific manner and prevents binding of NF-B (p65/p50) to its element. However, activation of the PARP-1 enzymatic activity enhances CXCL1 expression, owing to the loss of PARP-1 binding to the CXCL1 promoter, accompanied by enhanced binding of p65 to the promoter. The delineation of the role of NF-B-interacting factors in the putative CXCL1 enhanceosome will provide key information in developing strategies to block constitutive expression of this and other chemokines in cancer and to develop targeted therapy.