Abstract
Previous studies have shown that wild-type human telomerase reverse transcriptase (hTERT) protein can functionally replace the human papillomavirus type 16 (HPV-16) E6 protein, which cooperates with the viral E7 protein in the immortalization of primary keratinocytes. In the current study, we made the surprising finding that catalytically inactive hTERT (hTERT-D868A), elongation-defective hTERT (hTERT-HA), and telomere recruitment-defective hTERT (hTERT N+T) also cooperate with E7 in mediating bypass of the senescence blockade and effecting cell immortalization. This suggests that hTERT has activities independent of its telomere maintenance functions that mediate transit across this restriction point. Since hTERT has been shown to have a role in gene activation, we performed microarray studies and discovered that E6, hTERT and mutant hTERT proteins altered the expression of highly overlapping sets of cellular genes. Most important, the E6 and hTERT proteins induced mRNA and protein levels of Bmi1, the core subunit of the Polycomb Group (PcG) complex 1. We show further that Bmi1 substitutes for E6 or hTERT in cell immortalization. Finally, tissue array studies demonstrated that expression of Bmi1 increased with the severity of cervical dysplasia, suggesting a potential role in the progression of cervical cancer. Together, these data demonstrate that hTERT has extra-telomeric activities that facilitate cell immortalization and that its induction of Bmi1 is one potential mechanism for mediating this activity.
Highlights
Cell immortality is a hallmark of cancer cells [1] and the highrisk oncogenic human papillomaviruses (HPVs) encode two major transforming genes, E6 and E7, which are required for the immortalization of human primary genital keratinocytes [2,3]
In the current study we show that the enzymatic activity of human telomerase reverse transcriptase (hTERT) is not required for cooperating in cell immortalization
We further demonstrate that hTERT proteins increase the expression of the Bmi1 protein, which is capable of cooperating in cell immortalization
Summary
Cell immortality is a hallmark of cancer cells [1] and the highrisk oncogenic HPVs encode two major transforming genes, E6 and E7, which are required for the immortalization of human primary genital keratinocytes [2,3]. The absence of telomerase activity in most normal human cells results in the progressive shortening of telomeres with each cell division [12,13], leading to chromosomal instability and cellular replicative senescence [12,14]. For this reason, telomere shortening is thought to represent the ‘‘mitotic clock’’ that determines cellular lifespan. Especially those with decreased function of the p16/Rb pathway, telomerase activity is sufficient to bypass both M1 and M2 blockades and to stabilize and elongate telomeres [17,18,19,20]
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