Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease
| Autor: | Kayla McEnery, Jili Zhu, Binghua Li, Peter Igarashi, Alysha Rauhauser, Komal Vadnagara, Dongmei Lu, Sarah Elhadi, Massimo Attanasio, Chongyu Ren, Moumita Chaki, Anton M. Jetten |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Senescence medicine.medical_specialty Kruppel-Like Transcription Factors Fluorescent Antibody Technique Kinesins Nerve Tissue Proteins Biology Article Piperazines Mice 03 medical and health sciences Cystic kidney disease 0302 clinical medicine Nephronophthisis Internal medicine Null cell medicine Animals Humans Cilia CHEK1 RNA Small Interfering Cellular Senescence Mice Knockout Cystic kidney Cysts Imidazoles Epithelial Cells Proto-Oncogene Proteins c-mdm2 Cell Cycle Checkpoints Kidney Diseases Cystic Cell cycle Flow Cytometry medicine.disease Fibrosis Disease Models Animal Kidney Tubules Phenotype 030104 developmental biology Endocrinology Nephrology 030220 oncology & carcinogenesis Checkpoint Kinase 1 Knockout mouse Cancer research RNA Interference Tumor Suppressor Protein p53 DNA Damage |
| Zdroj: | Kidney International. 89:1307-1323 |
| ISSN: | 0085-2538 |
| Popis: | Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest. |
| Databáze: | OpenAIRE |
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