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Allen Taylor, Sheldon Rowan, Min-Lee Chang, Fu Shang, Natalie Reznikov, Lei Lyu, Ke Liu; Lens differentiation rides the wave of p27Kip1 to lens fiber cell denucleation. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
The eye lens is unique among tissues. Using the same building blocks as are used to create the opaque tissues, the lens is clear. It does not form tumors, and the majority of its cells destroy their organelles, including their nuclei. A mystery for over a century, there has been considerable recent progress in elucidating mechanisms of lens fiber cell denucleation (LFCD). The cumulative evidence indicates that the unidirectional process of LFCD utilizes cellular machinery from the cyclic events of mitosis to initiate nuclear envelope breakdown.
Using cell free and in vitro cell culture systems, as well as laboratory animals, along with biochemical, and histologic techniques, including Focused Ion Beam Electron Microscopy, we monitored the cyclin-dependent kinase inhibitor, p27Kip1, cyclin-dependent kinase 1 (Cdk1), nuclear lamins, DNaseIIβ (DLAD), ubiquitin proteasome system (UPS) and the unfolded protein response (UPR), Calcium, calpain activity, and cell nucleus disassembly.
Multiple cellular pathways, including the UPS and the UPR, converge on post-translational regulation of p27Kip1. p27Kip1 is degraded, liberating a wave of Cdk1 activity. This results in phosphorylation of nuclear lamins, dissociation of the nuclear membrane, and entry of lysosomes that liberate DLAD to cleave chromatin. Failed UPS results in stabilization of p27Kip1; inhibition of Cdk1 activity; stabilization of Connexin 46; elevation of Ca2+, elevation of calpain activity, unscheduled, cataract-related cleavage of multiple major lens proteins; and a delayed differentiation program associated with lack of LFCD. Mouse models with an activated UPR in the lens also exhibited stabilized p27Kip1, inhibition of Cdk1 activity, failed LFCD, and congenital cataract.
Mutations that impair these pathways cause congenital cataracts, associated with loss of LFCD. These findings highlight new regulatory nodes in the lens and suggest that we are close to understanding this fascinating final step in the most terminal differentiation process of the body. Such knowledge may offer a new means to confront proliferative diseases including cancer.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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