Abstract
The RNA-binding protein tristetraprolin (TTP) regulates expression of many cancer-associated and proinflammatory factors through binding AU-rich elements (ARE) in the 3'-untranslated region (3'UTR) and facilitating rapid mRNA decay. Here we report on the ability of TTP to act in an anti-proliferative capacity in HPV18-positive HeLa cells by inducing senescence. HeLa cells maintain a dormant p53 pathway and elevated telomerase activity resulting from HPV-mediated transformation, whereas TTP expression counteracted this effect by stabilizing p53 protein and inhibiting hTERT expression. Presence of TTP did not alter E6 and E7 viral mRNA levels indicating that these are not TTP targets. It was found that TTP promoted rapid mRNA decay of the cellular ubiquitin ligase E6-associated protein (E6-AP). RNA-binding studies demonstrated TTP and E6-AP mRNA interaction and deletion of the E6-AP mRNA ARE-containing 3'UTR imparts resistance to TTP-mediated downregulation. Similar results were obtained with high-risk HPV16-positive cells that employ the E6-AP pathway to control p53 and hTERT levels. Furthermore, loss of TTP expression was consistently observed in cervical cancer tissue compared to normal tissue. These findings demonstrate the ability of TTP to act as a tumor suppressor by inhibiting the E6-AP pathway and indicate TTP loss to be a critical event during HPV-mediated carcinogenesis.
Highlights
Cervical cancer is the second most common cancer among women worldwide [1]
Consistent with other findings [24, 25], endogenous TTP expression was undetectable in HeLa cells and in HeLa Tet-Off parental cells grown in the presence or absence of Dox (Figure 1A and data not shown)
To determine the consequence of TTP expression, we evaluated the ability of TTP to attenuate HeLa cell growth and proliferation
Summary
A necessary factor in the development of most cases of cervical cancer is infection with the high-risk human papillomavirus (HPV) types 16 and 18 [2]. These subtypes of HPV promote cellular transformation through expression of the early viral genes E6 and E7. E6-AP belongs to a class of HECT ubiquitin-protein ligases [9] and its interaction with E6 facilitates cell transformation through enhanced p53 protein degradation and activation of hTERT gene expression [10] Deregulation of these critical factors through the combined action of E6 and E7 oncoproteins allows for continued cell proliferation and genomic instability leading to HPV-mediated cellular transformation
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