Regulation of telomerase by human papillomaviruses.
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.
Galloway
D A
DA
Program in Cancer Biology, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Gewin
L C
LC
Myers
H
H
Luo
W
W
Grandori
C
C
Katzenellenbogen
R A
RA
McDougall
J K
JK
D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000821:virology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology; D030361:Papillomavirus Infections / Q000209:etiology; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000209:etiology
D004268:DNA-Binding Proteins; C489427:MYC protein, human; C492666:NFX1 protein, human; D009856:Oncogene Proteins, Viral; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D019098:Telomerase