Open AccessRegulation of Telomerase by Human Papillomaviruses
Author(s) -
Denise A. Galloway,
Lindy Gewin,
Hadley E. Myers,
WeiSheng Luo,
Carla Grandori,
Rachel A. Katzenellenbogen,
James K. McDougall
Publication year - 2005
Publication title -
cold spring harbor symposia on quantitative biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.615
H-Index - 77
eISSN - 1943-4456
pISSN - 0091-7451
DOI - 10.1101/sqb.2005.70.041
Subject(s) - telomerase , ubiquitin ligase , gene isoform , telomerase reverse transcriptase , protein subunit , transcription (linguistics) , microbiology and biotechnology , carcinogenesis , histone , chemistry , telomere , transcription factor , ubiquitin , biology , dna , biochemistry , gene , linguistics , philosophy
The E6 oncoprotein of human papillomaviruses (HPVs) induces telomerase activity in primary human epithelial cells. This activity is dependent on association of E6 with E6AP, a cellular ubiquitin ligase. E6 activates the transcription of hTERT, the catalytic subunit of telomerase. E boxes near the start of hTERT transcription are required for E6; however, acetylated histones are only present in the E6 cells. We identified two isoforms of NFX1, a new binding partner of E6/E6AP. The NFX1- 91 isoform binds to an X-box motif located adjacent to the proximal E box, binds Sin3A and HDACs, repressing hTERT transcription. It preferentially binds E6/E6AP and is targeted for ubiquitin-mediated degradation. The NFX1-123 isoform has the opposite activity, increasing hTERT transcription or translation. This is the first example of viral oncoproteins disrupting regulation of telomerase, a critical event in tumorigenesis.
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