title: Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract.
abstract: Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-specific mutations that elicit an unfolded-protein response (UPR) in vivo accumulate p27(Cdkn1b), show cyclin-dependent kinase (Cdk)-1 inhibition, retain their LFC nuclei, and are cataractous. Although a UPR was not detected in lenses expressing K6W-Ub, they also accumulated p27 and showed failed LFCD. Induction of a UPR in human lens epithelial cells (HLECs) also induced accumulation of p27 associated with decreased levels of S-phase kinase-associated protein (Skp)-2, a ubiquitin ligase that regulates mitosis. These cells also showed decreased lamin A/C phosphorylation and metaphase arrest. The suppression of lamin A/C phosphorylation and metaphase transition induced by the UPR was rescued by knockdown of p27. Taken together, these data indicate that accumulation of p27, whether related to the UPR or not, prevents the phosphorylation of lamin A/C and LFCD in maturing LFCs in vivo, as well as in dividing HLECs. The former leads to cataract and the latter to metaphase arrest. These results suggest that accumulation of p27 is a common mechanism underlying retention of LFC nuclei.
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lyu
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Whitcomb
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Jiang
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Min-Lee
authors.initials: ML
authors.lastname: Chang
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Gu
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Duncan
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Ales
authors.initials: A
authors.lastname: Cvekl
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Wang
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Limi
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Lixing W
authors.initials: LW
authors.lastname: Reneker
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
authors.forename: Fu
authors.initials: F
authors.lastname: Shang
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA allen.taylor@tufts.edu dulinfang@scu.edu.cn.
authors.forename: Linfang
authors.initials: L
authors.lastname: Du
authors.affiliation: *Ministry of Education Key Laboratory of Bio-resource and Eco-environment, College of Life Science, Sichuan University, Sichuan China; Laboratory for Nutrition and Vision Research, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA; Department of Biological Sciences, University of Delaware, Newark, Delaware, USA; Department of Genetics and Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA allen.taylor@tufts.edu dulinfang@scu.edu.cn.
authors.forename: Allen
authors.initials: A
authors.lastname: Taylor
mesh_terms: D000818:Animals; D002386:Cataract / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D034904:Lamin Type A; D044786:S-Phase Kinase-Associated Proteins; C440308:lamin C; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: cell cycle; endoplasmic reticulum stress; nuclear disassembly; ubiquitin