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.

journal_name

Oncogene

journal_title

Oncogene

authors

Ndisang D,Khan A,Lorenzato F,Sindos M,Singer A,Latchman DS

doi

10.1038/onc.2010.33

subject

Has Abstract

pub_date

2010-05-06 00:00:00

pages

2701-11

issue

18

eissn

0950-9232

issn

1476-5594

pii

onc201033

journal_volume

29

pub_type

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