The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix.

Abstract

The cellular transcription factor Brn-3a differentially regulates different human papilloma virus (HPV)-16 variants that are associated with different risks of progression to cervical carcinoma in infected humans. The upstream regulatory regions (URRs) of high- and intermediate-risk HPV-16 variants are activated by the cellular transcription factor Brn-3a, whereas the URR of a low-risk HPV-16 variant is not. In this study, we show in transfection assays that Brn-3a and the smoking-related substance nicotine produce stronger responsiveness of the URR of the low- and high-risk variants than with either factor alone, but not the intermediate-risk variant. We determined that this synergistic activity of Brn-3a/nicotine is due to two nucleotide differences in the URR, crucial for oncogenic E6/E7 transactivation. Mutant constructs in which the nucleotide residues were substituted alter Brn-3a/nicotine responsiveness. Importantly, women smokers with high levels of Brn-3a infected with low- or high-risk HPV-16 variants have augmented E6 levels, and were more frequently diagnosed with higher grades of cervical intraepithelial neoplasia (CIN) and cancer, as compared with non-smokers who were infected with similar variants and expressed similar levels of Brn-3a. Therefore, this study defines the specific interplay between the cellular transactivator Brn-3a, the environmental smoking-related substance nicotine and specific HPV variants in cervical carcinogenesis, and thus helps to explain why some women are susceptible to rapid CIN progression and cancer and others are not.

• Authors: D Ndisang, A Khan, F Lorenzato, M Sindos, A Singer, D S Latchman
• Journal: Oncogene (Oncogene) Vol. 29 Issue 18 Pg. 2701-11 (May 06 2010) ISSN: 1476-5594 [Electronic] England
• PMID: 20190800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E6 protein, Human papillomavirus type 16
• Oncogene Proteins, Viral
• Papillomavirus E7 Proteins
• Repressor Proteins
• Transcription Factor Brn-3A
• oncogene protein E7, Human papillomavirus type 16
• Nicotine

Topics

• Cervix Uteri (virology)
• Female
• Human papillomavirus 16 (genetics)
• Humans
• Nicotine (pharmacology)
• Oncogene Proteins, Viral (physiology)
• Papillomavirus E7 Proteins (physiology)
• Repressor Proteins (physiology)
• Smoking (adverse effects)
• Transcription Factor Brn-3A (physiology)
• Uterine Cervical Neoplasms (etiology)
• Uterine Cervical Dysplasia (etiology)