Cell immortalization is a critical event in the development of cancer and the oncogenic human papillomaviruses encode an E6 oncogene that is primarily responsible for inducing telomerase activity and consequent immortalization. Recent studies indicate that the HPV E6 protein mediates the increase in telomerase activity via its ability to engage and activate the hTERT promoter and interact directly with at least two promoter-bound proteins, Myc and NFX-1. E6 also has a post-translational mechanism to increase telomerase activity by binding directly to hTERT proteins. In the current grant, we show that hTERT immortalization of primary keratinocytes is independent of its telomerase activity or ability to elongate telomeres. In agreement with recent work with stem cells, our new preliminary findings demonstrate that hTERT can alter the expression of keratinocyte genes as well as increase the expression of HPV genes. We hypothesize that the transcription activation function of hTERT or its potential role in altering apoptotic responses may play an essential role in bypassing the M1/M2 restriction points in cell proliferation and thereby facilitate cell immortalization. In this application, we will evaluate these possibilities using a library of mutan hTERT expression vectors. We will correlate the ability of these mutant proteins to efficiently bypass cellular senescence with their ability to induce reverse transcriptase activity, hTR binding, telomere binding, telomere elongation, promoter transactivation, and modulation of apoptosis. These studies will provide new insights into a basic event in the etiology of cancer.

Public Health Relevance

Papillomaviruses have an important role in human cancer, especially cervical, anal and oral cancer. These viruses induce uncontrolled growth of the infected cells, which with time, results in the eventual progression to cancer. We are studying the mechanisms by which the papillomavirus genes induce uncontrolled cell growth. One likely explanation is that the viral E6 gene increases the expression of telomerase protein in host cells, a protein that has a critical role in both cancer and aging. The study of the telomerase wil eventually allow us to develop methods and drugs to treat these tumors.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA180524-02
Application #
8685210
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgetown University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20057
Assefnia, Shahin; Kang, Keunsoo; Groeneveld, Svenja et al. (2014) Trp63 is regulated by STAT5 in mammary tissue and subject to differentiation in cancer. Endocr Relat Cancer 21:443-57
Zheng, Yun-Ling; Zhang, Fan; Sun, Bing et al. (2014) Telomerase enzymatic component hTERT shortens long telomeres in human cells. Cell Cycle 13:1765-76