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Nat Commun. 2018 Sep 6;9(1):3613. doi: 10.1038/s41467-018-05808-y.

Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation.

Zhang Y1,2, Wang J1,2, Huang W2, Cai J2,3, Ba J4, Wang Y1,2, Ke Q2, Huang Y1,2, Liu X1,2, Qiu Y1,2, Lu Q1,2, Sui X1,2, Shi Y1,2, Wang T1,2, Shen H5, Guan Y6, Zhou Y7, Chen Y8, Wang M9, Xiang AP10,11,12.

Author information

1
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510623, China.
2
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China.
3
Department of Hepatic Surgery and Liver transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University, Guangzhou, 510630, China.
4
Department of Medical Intensive Unit, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China.
5
Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
6
Core Facility Center, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, 510080, China.
7
Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
8
Center for Neurobiology, School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
9
The Cardiovascular Center, Gaozhou People's Hospital, Maoming, 525200, China. mmwmsmd@126.com.
10
Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510623, China. xiangp@mail.sysu.edu.cn.
11
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, China. xiangp@mail.sysu.edu.cn.
12
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510080, China. xiangp@mail.sysu.edu.cn.

Abstract

Emerging evidence has revealed that Nestin not only serves as a biomarker for multipotent stem cells, but also regulates cell proliferation and invasion in various tumors. However, the mechanistic contributions of Nestin to cancer pathogenesis are still unknown. In the present study, previously thought to reside exclusively in the cytoplasm, Nestin can also be found in the nucleus and participate in protecting tumor cells against cellular senescence. Specifically, we reveal that Nestin has a nuclear localization signal (aa318-aa347) at the downstream of rod domain. We then find nuclear Nestin could interact with lamin A/C. Mechanistic investigations demonstrate that Nestin depletion results in the activation of cyclin-dependent kinase 5 (Cdk5), which causes the phosphorylation of lamin A/C (mainly at S392 site) and its subsequent translocation to the cytoplasm for degradation. The findings establish a role for nuclear Nestin in tumor senescence, which involves its nucleus-localized form and interaction with lamin A/C.

PMID:
30190500
PMCID:
PMC6127343
DOI:
10.1038/s41467-018-05808-y
[Indexed for MEDLINE]
Free PMC Article

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