Cellular immortalization is considered a primary and early event for the  development of cancer.  The molecular basis for immortalization is not fully understood.  Activation of human telomerase reverse transcriptase (hTERT) has been considered as the mechanism for the extension of cell lifespan.  However, several recent observations challenged the role of catalytic activity of telomerase in this process.  Telomere protection in addition to telomere elongation by hTERT is now believed to play a major role for immortalization. 

The human papillomavirus (HPV) E6 oncogene efficiently immortalizes human mammary epithelial cells (HMECs) and cooperates with HPV E7 to immortalize human keratinocytes.  Inactivation of p53 was initially considered to be the mechanism by which E6 induces immortalization. Subsequent studies demonstrated p53-independent immortalization activity of E6.  The prevailing model is that E6 turns on the transciption of hTERT to induce cellular immortalization.  Since E6 can activate the c-myc promoter and hTERT is a direct transcriptional target of c-myc, it is proposed that E6 activates telomerase through induction of c-myc expression.  However, several lines of evidence indicate that c-myc-dependent transcription may not be essential for E6-mediated upregulation of hTERT.  Moreover, telomere shortening has been observed in E6-immortalized cells.  In this review, we will summarize our current understanding of cellular immortalization by E6 and discuss potential mechanism by which E6 induces immortalization.