title: GRIM-19 Restores Cervical Cancer Cell Senescence by Repressing hTERT Transcription.
abstract: High telomerase activity promotes tumor growth by stabilizing damaged chromosomes and their mitotic replication. Overactivation of telomerase activity has been reported in cervical cancer, a malignancy caused by high-risk human papillomaviruses (HR-HPVs). The HR-HPV E6 can activate hTERT promoter by interacting with E6AP or other binding proteins and by stabilizing the interaction between hTERT and E6AP. GRIM-19 is a novel tumor suppressor that affects multiple targets in a cell to regulate growth. We have previously reported the interaction of GRIM-19 with 18E6 and E6AP to disrupt the E6/E6AP complex and increase the autoubiquitination of E6AP. In this study, we characterized the interaction of GRIM-19 with 16E6 (an oncoprotein produced by HPV16) and identified the binding sites that mediate this interaction. We also found that GRIM-19 expression in cervical cancer cells could inhibit telomerase activity by inhibiting the transactivation of the hTERT promoter by E6, thereby promoting cervical cancer cell senescence. Moreover, we identified a negative correlation between GRIM-19 and hTERT expression in cervical cancer tissues. Suppression of GRIM-19 and induction of hTERT levels were associated with lymph node metastasis, advanced clinical stage, and poor prognosis. This study identified another important novel antitumor molecular link associated with GRIM-19 in the tumorigenesis.
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Feng
authors.initials: F
authors.lastname: Tao
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Dingqing
authors.initials: D
authors.lastname: Feng
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Bin
authors.initials: B
authors.lastname: Ling
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Lili
authors.initials: L
authors.lastname: Qian
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Huiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1 Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhao
authors.affiliation: 2 Department of Oncological Radiotherapy, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China .
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: 3 Hefei National Laboratory for Physical Sciences, Microscale and School of Life Sciences, University of Science and Technology of China , Hefei, Anhui, China .
authors.forename: Ge
authors.initials: G
authors.lastname: Shan
authors.affiliation: 4 Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Dhan V
authors.initials: DV
authors.lastname: Kalvakolanu
authors.affiliation: 3 Hefei National Laboratory for Physical Sciences, Microscale and School of Life Sciences, University of Science and Technology of China , Hefei, Anhui, China .
authors.forename: Weihua
authors.initials: W
authors.lastname: Xiao
mesh_terms: D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; C509186:TERT protein, human; D019098:Telomerase