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. 2000 Jul 6;19(29):3235-44. doi: 10.1038/sj.onc.1203643.

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-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Cell Nucleus / metabolism
  • Chemokine CCL2 / genetics*
  • Chromatin / physiology*
  • Chromosome Mapping
  • Deoxyribonuclease I / metabolism
  • Gene Expression Regulation* / drug effects
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Papillomaviridae / genetics*
  • RNA, Messenger
  • Sequence Analysis, DNA
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Chemokine CCL2
  • Chromatin
  • RNA, Messenger
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Deoxyribonuclease I

Associated data

  • GENBANK/Y18933