P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma
| Autor: | Carolyn Zin, Pamela L. Mellon, Jing Luo, Danni Lin, Michael Ai, Wenqiu Wang, Ling Zhao, Daniel Chen, Michael G. Rosenfeld, Zheng Zhong, Liangfang Zhang, Ken Flagg, William Shi, Emily Yeh, Kang Zhang, Jie Zhu, Catherine Shi, Yizhi Liu, Maryam Jafari, Sherrina Patel, Sheng Zhong, Ruben Abagyan, Lianghong Zheng, Gen Li, Yanxin Xu, Hongrong Luo, Dorota Skowronska-Krawczyk, Robert N. Weinreb, Weiwei Gao, Guiqun Cao, Cindy Wen, Martin Krupa, Jin Zhu, Hong Ouyang, Christopher Chung, Yehong Zhuo, Xiaodong Sun, Michal Krawczyk, Oulan Li |
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| Rok vydání: | 2015 |
| Předmět: |
Retinal Ganglion Cells
Aging genetic structures Glaucoma Neurodegenerative Inbred C57BL Eye Medical and Health Sciences Pathogenesis Mice 2.1 Biological and endogenous factors Aetiology Mice Knockout Cell Death Biological Sciences Up-Regulation Open-Angle medicine.anatomical_structure Retinal ganglion cell Glaucoma Open-Angle Gene isoform Senescence Programmed cell death Knockout Molecular Sequence Data Mutation Missense Biology Cell Line Downregulation and upregulation Genetics medicine Genetic predisposition Animals Humans Amino Acid Sequence Eye Disease and Disorders of Vision neoplasms Molecular Biology Cyclin-Dependent Kinase Inhibitor p16 Homeodomain Proteins Human Genome Neurosciences Cell Biology medicine.disease eye diseases Mice Inbred C57BL Case-Control Studies Mutation Trans-Activators Cancer research sense organs Missense Developmental Biology |
| Zdroj: | Molecular Cell, vol 59, iss 6 Molecular cell, vol 59, iss 6 Skowronska-Krawczyk, D; Zhao, L; Zhu, J; Weinreb, RN; Cao, G; Luo, J; et al.(2015). P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma. Molecular Cell, 59(6), 931-940. doi: 10.1016/j.molcel.2015.07.027. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/2wj3h2qz |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2015.07.027 |
| Popis: | © 2015 Elsevier Inc. Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. Zhang et al. report p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age, and intraocular pressure, in the pathogenesis of glaucoma. They demonstrate that upregulation of SIX6 upon stress directly increases p16INK4a, leading to retinal ganglion cell senescence and death. |
| Databáze: | OpenAIRE |
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