Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract

Lei Lyu, Elizabeth A. Whitcomb, Shuhong Jiang, Min Lee Chang, Yumei Gu, Melinda K. Duncan, Ales Cvekl, Wei Lin Wang, Saima Limi, Lixing W. Reneker, Fu Shang, Linfang Du, Allen Taylor

Research output: Contribution to journalArticle

12 Scopus citations

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 kinaseassociated protein (Skp)-2, a ubiquitin ligase that regulatesmitosis. 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.

Original languageEnglish (US)
Pages (from-to)1087-1095
Number of pages9
JournalFASEB Journal
Volume30
Issue number3
DOIs
StatePublished - Mar 2016

Keywords

  • Cell cycle
  • Endoplasmic reticulum stress
  • Nuclear disassembly
  • Ubiquitin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Lyu, L., Whitcomb, E. A., Jiang, S., Chang, M. L., Gu, Y., Duncan, M. K., Cvekl, A., Wang, W. L., Limi, S., Reneker, L. W., Shang, F., Du, L., & Taylor, A. (2016). Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. FASEB Journal, 30(3), 1087-1095. https://doi.org/10.1096/fj.15-278036