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Differential transcriptional regulation of the monocyte-chemoattractant protein-1 (MCP-1) gene in tumorigenic and non-tumorigenic HPV 18 positive cells: The role of the chromatin structure and AP-1 composition

Abstract

The expression of the monocyte-chemoattractant-protein-1 (MCP-1) is closely linked with a non-tumorigenic phenotype in somatic cell hybrids made between the human papillomavirus type 18 (HPV 18) positive cervical carcinoma cell line HeLa and normal human fibroblasts. In contrast, MCP-1 transcription is absent in tumorigenic segregants derived from the same hybrids or in parental HeLa cells. Selectivity of MCP-1 transcription, which is regulated at the level of initiation of transcription, is mainly based on differences in the location and extension of DNAse I-hypersensitive regions (DHSR) at both ends of the gene. While TNF-α only moderately increases the sensitivity of pre-existing 5′-DHSRs, a 3′-end DHSR became strongly induced exclusively in non-malignant hybrids. DNA sequencing showed that the 3′-DHSR coincides with an additional AP-1 site located approximately 600 bp downstream of the polyadenylation site. Analyses of AP-1 composition revealed that MCP-1 is only expressed in those cells where jun-family members were mainly heterodimerized with the fos-related protein fra-1. In contrast, in tumorigenic cells the 1 : 1 ratio between jun and fra-1 is disturbed and the MCP-1 gene is no longer expressed. Hence, alterations in the heterodimerization pattern of AP-1 and its selective accessibility to opened chromatin may represent a novel regulatory pathway in the regulation of chemokines in malignant and non-malignant HPV-positive cells.

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Acknowledgements

The authors thank Dr Eric Stanbridge (University of Irvine, CA, USA) for providing the somatic cell hybrids. The excellent technical help of Maike Lengert is appreciated. Dr Ubaldo Soto was supported by the Alexander von Humboldt Stiftung. This work was supported by the Concerted Action Contract No BIO4-CT98-0097 of the European Community.

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Finzer, P., Soto, U., Delius, H. et al. Differential transcriptional regulation of the monocyte-chemoattractant protein-1 (MCP-1) gene in tumorigenic and non-tumorigenic HPV 18 positive cells: The role of the chromatin structure and AP-1 composition . Oncogene 19, 3235–3244 (2000). https://doi.org/10.1038/sj.onc.1203643

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