Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin.
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either TSC1 or TSC2 tumor suppressor gene. TSC1 and TSC2 products, Harmatin and Tuberin, form the functional complex to serve as the negative regulator for insulin-induced phosphorylation of S6 kinase and elF4E-binding protein 1. High-risk human papillomavirus (HPV) infection is the necessary cause for cervical cancer. E6 oncoprotein encoded by HPV plays a pivotal role in carcinogenesis by interference with the host intracellular protein functions. In this study, we show that HPV16 E6 interacts with tumor suppressor gene TSC2 product, Tuberin, and results in the phosphorylation of S6 kinase and S6 even in the absence of insulin. The overexpression of Tuberin overcomes the effect of E6 on S6 kinase phosphorylation. Binding with HPV16 E6 causes the proteasome-mediated degradation of Tuberin. A DILG motif and an ELVG motif located in the carboxyl-terminal of Tuberin are required for E6 binding. In addition, the Tuberin interaction region in E6 has been mapped in the amino-terminal portion of HPV16 E6, which is different from the binding domain with p53. These results provide a possible link between E6-induced oncogenesis and the insulin-stimulated cell proliferation signaling pathway.
Lu
Zheming
Z
Department of Genetics, Beijing Institute for Cancer Research, School of Oncology, Peking University, 1 Da Hong Luo Chang Street, West District, Beijing 100034, People's Republic of China.
Hu
Xiuhua
X
Li
Yong
Y
Zheng
Li
L
Zhou
Yue
Y
Jiang
Haidi
H
Ning
Tao
T
Basang
Zhuoma
Z
Zhang
Chunfeng
C
Ke
Yang
Y
D000818:Animals; D001665:Binding Sites; D016147:Genes, Tumor Suppressor; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014402:Tuberous Sclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D014412:Tumor Virus Infections / Q000209:etiology / Q000235:genetics / Q000378:metabolism
C068651:E6 protein, Human papillomavirus type 16; D007328:Insulin; D009856:Oncogene Proteins, Viral; D011506:Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D019893:Ribosomal Protein S6 Kinases