Abstract
ZNF313 encoding a zinc-binding protein is located at chromosome 20q13.13, which exhibits a frequent genomic amplification in multiple human cancers. However, the biological function of ZNF313 remains largely undefined. Here we report that ZNF313 is an ubiquitin E3 ligase that has a critical role in the regulation of cell cycle progression, differentiation and senescence. In this study, ZNF313 is initially identified as a XIAP-associated factor 1 (XAF1)-interacting protein, which upregulates the stability and proapoptotic effect of XAF1. Intriguingly, we found that ZNF313 activates cell cycle progression and suppresses cellular senescence through the RING domain-mediated degradation of p21WAF1. ZNF313 ubiquitinates p21WAF1 and also destabilizes p27KIP1 and p57KIP2, three members of the CDK-interacting protein (CIP)/kinase inhibitor protein (KIP) family of cyclin-dependent kinase inhibitors, whereas it does not affect the stability of the inhibitor of CDK (INK4) family members, such as p16INK4A and p15INK4B. ZNF313 expression is tightly controlled during the cell cycle and its elevation at the late G1 phase is crucial for the G1-to-S phase transition. ZNF313 is induced by mitogenic growth factors and its blockade profoundly delays cell cycle progression and accelerates p21WAF1-mediated senescence. Both replicative and stress-induced senescence are accompanied with ZNF313 reduction. ZNF313 is downregulated during cellular differentiation process in vitro and in vivo, while it is commonly upregulated in many types of cancer cells. ZNF313 shows both the nuclear and cytoplasmic localization in epithelial cells of normal tissues, but exhibits an intense cytoplasmic distribution in carcinoma cells of tumor tissues. Collectively, ZNF313 is a novel E3 ligase for p21WAF1, whose alteration might be implicated in the pathogenesis of several human diseases, including cancers.
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Abbreviations
- BMP:
-
bone morphogenetic protein
- CDK:
-
cyclin-dependent kinase
- CIP:
-
CDK-interacting protein
- IP:
-
immunoprecipitation
- INK4:
-
inhibitor of CDK
- KIP:
-
kinase inhibitor protein
- RT-PCR:
-
reverse transcription-polymerase chain reaction
- siRNA:
-
short-interfering RNA
- TGF:
-
transforming growth factor
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- UIM:
-
ubiquitin-interacting motif
- XAF1:
-
XIAP-associated factor 1
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Acknowledgements
For expert technical assistance and helpful discussions we are grateful to Jae-Sung Yi, Chang-Seok Lee and Young-Gyu Ko (Korea University, Seoul, South Korea). This work was supported in part by grants to SGC (2009-0078864 and 2009-0087099) and MGL (353-2009-2-C00071) from National Research Foundation of Korea.
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JH designed the study, performed the experiments and analyzed the data; YK, KWL, NGH, SIJ and JHL carried out molecular works; MJK and BKR analyzed human cancers; TKH performed statistical analyses; SY and JHB investigated brain development and designed a part of the study. SGC and MGL obtained funding, designed the study and wrote the manuscript.
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Han, J., Kim, YL., Lee, KW. et al. ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21WAF1. Cell Death Differ 20, 1055–1067 (2013). https://doi.org/10.1038/cdd.2013.33
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DOI: https://doi.org/10.1038/cdd.2013.33
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