title: SIP1 is a downstream effector of GADD45G in senescence induction and growth inhibition of liver tumor cells.
abstract: Cellular senescence evasion caused by the inactivation of tumor suppressive programs is implicated in tumor initiation and therapeutic resistance. Our previous study has shown that the downregulation of growth arrest and DNA damage 45G (GADD45G) contributes to senescence bypass in hepatocellular carcinoma (HCC). Here, we report that the Smad-interacting protein-1 (SIP1) is transcriptionally activated and functions critically in the GADD45G-induced tumor cell senescence. Knockdown of SIP1 significantly abrogates the suppressive effects of GADD45G on the growth of xenografted liver tumor in vivo. The essential role of SIP1 in GADD45G activities is further validated in the model of the proteasome inhibitor MG132-induced cell senescence. We further show that JNK but not p38 MAPK activation is involved in the GADD45G-mediated SIP1 upregulation, and that JNK inhibition counteracts the GADD45G-induced cellular senescence. More importantly, we show that GADD45G and SIP1 expression are coincidently downregulated in primary human HCC tissues. Together, our results establish that the dowregulation of GADD45G-SIP1 axis may contribute to cellular senescence evasion and HCC development.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Guiqin
authors.initials: G
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Aihui
authors.initials: A
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Boshi
authors.initials: B
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Zhaojuan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000074165:Zinc Finger E-box Binding Homeobox 2; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D048670:MAP Kinase Kinase 4; D012097:Repressor Proteins; D000074165:Zinc Finger E-box Binding Homeobox 2; D000097642:GADD45 Proteins; C492363:ZEB2 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: GADD45G; SIP1; cell senescence; hepatocellular carcinoma