The mRNA decay factor tristetraprolin (TTP) induces senescence in human papillomavirus-transformed cervical cancer cells by targeting E6-AP ubiquitin ligase.
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.
Department of Biological Sciences and Cancer Research Center, University of South Carolina, Columbia, SC 29203, USA.
Sandhya
S
Sanduja
Vimala
V
Kaza
Dan A
DA
Dixon
D020413:3' Untranslated Regions / Q000235:genetics; D052685:Alphapapillomavirus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D002584:Cervix Uteri / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004848:Epithelium / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006207:Half-Life; D006367:HeLa Cells; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000821:virology; D001616:beta-Galactosidase / Q000378:metabolism
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012097:Repressor Proteins; D051816:Tristetraprolin; D016159:Tumor Suppressor Protein p53; C497552:ZFP36 protein, human; C034811:tetracycline resistance-encoding transposon repressor protein; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; C509186:TERT protein, human; D019098:Telomerase; D001616:beta-Galactosidase