title: Disassembly of the lens fiber cell nucleus to create a clear lens: The p27 descent.
abstract: The eye lens is unique among tissues: it is transparent, does not form tumors, and the majority of its cells degrade their organelles, including their cell nuclei. A mystery for over a century, there has been considerable recent progress in elucidating mechanisms of lens fiber cell denucleation (LFCD). In contrast to the disassembly and reassembly of the cell nucleus during mitosis, LFCD is a unidirectional process that culminates in destruction of the fiber cell nucleus. Whereas p27Kip1, the cyclin-dependent kinase inhibitor, is upregulated during formation of LFC in the outermost cortex, in the inner cortex, in the nascent organelle free zone, p27Kip1is degraded, markedly activating cyclin-dependent kinase 1 (Cdk1). This process results in phosphorylation of nuclear Lamins, dissociation of the nuclear membrane, and entry of lysosomes that liberate DNaseIIβ (DLAD) to cleave chromatin. Multiple cellular pathways, including the ubiquitin proteasome system and the unfolded protein response, converge on post-translational regulation of p27Kip1. Mutations that impair these pathways are associated with congenital cataracts and loss of LFCD. These findings highlight new regulatory nodes in the lens and suggest that we are close to understanding this fascinating terminal differentiation process. Such knowledge may offer a new means to confront proliferative diseases including cancer.
authors.affiliation: Tufts University JM-USDA Human Nutrition Research Center on Aging, Laboratory of Nutrition and Vision Research, 711 Washington Street Boston, MA, 02111, USA. Electronic address: sheldon.rowan@tufts.edu.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Rowan
authors.affiliation: Tufts University JM-USDA Human Nutrition Research Center on Aging, Laboratory of Nutrition and Vision Research, 711 Washington Street Boston, MA, 02111, USA. Electronic address: min-lee.chang@tufts.edu.
authors.forename: Min-Lee
authors.initials: ML
authors.lastname: Chang
authors.affiliation: Imperial College London, Depart of Materials, Prince Consort Road, South Kensington, London, SW7 2AZ, UK. Electronic address: n.reznikov@imperial.ac.uk.
authors.forename: Natalie
authors.initials: N
authors.lastname: Reznikov
authors.affiliation: Tufts University JM-USDA Human Nutrition Research Center on Aging, Laboratory of Nutrition and Vision Research, 711 Washington Street Boston, MA, 02111, USA. Electronic address: allen.taylor@tufts.edu.
authors.forename: Allen
authors.initials: A
authors.lastname: Taylor
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002386:Cataract / Q000151:congenital / Q000201:enzymology / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D034882:Lamins / Q000378:metabolism; D007908:Lens, Crystalline / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D008938:Mitosis; D010766:Phosphorylation; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D034882:Lamins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase
keywords: Cataract; Denucleation; Lysosome; Mitosis; Nuclear envelope; Ubiquitin proteolytic system; Unfolded protein response; cdk1