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

The expression of the monocyte-chemoattractant-protein-1 (MCP-1) is closely linked with a non-tumorigenic phenotype in somatic cell hybrids made betwe en the human papillomavirus type 18 (HPV 18) positive cervical carcinoma ce ll line HeLa and normal human fibroblasts, In contrast, MCP-1 transcription is absent in tumorigenic segregants derived from the same hybrids or in pa rental HeLa cells. Selectivity of MCP-1 transcription, which is regulated a t the le, el 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-alpha only moderately increases the sensit ivity of pre-existing 5'-DHSRs, a 3'-end DHSR became strongly induced exclu sively in non-malignant hybrids, DNA sequencing showed that the 3'-DHSR coi ncides with an additional AP-1 site located approximately 600 bp downstream of the polyadenylation site. Analyses of AP-1 composition revealed that MC P-1 is only expressed in those cells where jun-family members were mainly h eterodimerized with the fos-related protein fra-1. In contrast, in tumorige nic cells the 1:1 ratio between jun and fra-1 is disturbed and the MCP-1 ge ne is no longer expressed. Hence, alterations in the heterodimerization pat tern of AP-1 and its selective accessibility to opened chromatin may repres ent a novel regulatory pathway in the regulation of chemokines in malignant and non-malignant HPV-positive cells.