Linear ubiquitin chain induces apoptosis and inhibits tumor growth
Autor: | Guifen Wang, Wandong Jiang, Ying Sun, Zhoushuai Qin, Wei Xiao |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Cancer Research DNA damage Injections Subcutaneous Recombinant Fusion Proteins Clinical Biochemistry Green Fluorescent Proteins Pharmaceutical Science Mice Nude Apoptosis Protein Engineering Transfection 03 medical and health sciences Mice Ubiquitin Proliferating Cell Nuclear Antigen Monoubiquitination Animals Humans Pharmacology Mice Inbred BALB C DNA synthesis biology Cell growth Chemistry Biochemistry (medical) Cell Cycle Cell Biology Cell cycle HCT116 Cells Xenograft Model Antitumor Assays Cell biology Proliferating cell nuclear antigen Gene Expression Regulation Neoplastic 030104 developmental biology HEK293 Cells Doxycycline Colonic Neoplasms biology.protein Ectopic expression Poly(ADP-ribose) Polymerases Tumor Suppressor Protein p53 Plasmids Signal Transduction |
Zdroj: | Apoptosis : an international journal on programmed cell death. 23(1) |
ISSN: | 1573-675X |
Popis: | Ubiquitination of proliferating cell nuclear antigen (PCNA) plays an important role in DNA damage response. Ectopic expression of PCNA fused at either terminus with ubiquitin (Ub) lacking two C-terminal glycine residues induces translesion DNA synthesis which resembles synthesis mediated by PCNA monoubiquitination. PCNA fused with Ub containing the C-terminal Gly residues at the C-terminus can be further polyubiquitinated in a Gly-dependent manner, which inhibits cell proliferation and induces ATR-dependent replication checkpoint. In this study, we surprisingly found that PCNA fused to a head-to-tail linear Ub chain induces apoptosis in a Ub chain length-dependent manner. Further investigation revealed that the apoptotic effect is actually induced by the linear Ub chain independently from PCNA, as the Ub chain fused to GFP or an epitope tag still efficiently induces apoptosis. It is revealed that the artificial linear Ub chain differs from endogenously encoded linear Ub chains in that its Ubs contain a Ub-G76S substitution, making the Ub chain resistant to cleavage by deubiquitination enzymes. We demonstrated in this study that ectopic expression of the artificial Ub chain alone in cultured human cancer cells is sufficient to inhibit tumor growth in a xenograft mouse model, making the linear Ub chain a putative anti-cancer agent. |
Databáze: | OpenAIRE |
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