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

11 Citations (Scopus)

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 1 2016

Fingerprint

Unfolded Protein Response
Cataract
Lenses
Stabilization
Fibers
Lamin Type A
Phosphorylation
Proteins
Metaphase
Epithelial Cells
CDC2 Protein Kinase
Ligases
Ubiquitin
S Phase
Mitosis
Mutation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. / Lyu, Lei; Whitcomb, Elizabeth A.; Jiang, Shuhong; Chang, Min Lee; Gu, Yumei; Duncan, Melinda K.; Cvekl, Ales; Wang, Wei Lin; Limi, Saima; Reneker, Lixing W.; Shang, Fu; Du, Linfang; Taylor, Allen.

In: FASEB Journal, Vol. 30, No. 3, 01.03.2016, p. 1087-1095.

Research output: Contribution to journalArticle

Lyu, L, Whitcomb, EA, Jiang, S, Chang, ML, Gu, Y, Duncan, MK, Cvekl, A, Wang, WL, Limi, S, Reneker, LW, 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, vol. 30, no. 3, pp. 1087-1095. https://doi.org/10.1096/fj.15-278036
Lyu, Lei ; Whitcomb, Elizabeth A. ; Jiang, Shuhong ; Chang, Min Lee ; Gu, Yumei ; Duncan, Melinda K. ; Cvekl, Ales ; Wang, Wei Lin ; Limi, Saima ; Reneker, Lixing W. ; Shang, Fu ; Du, Linfang ; Taylor, Allen. / Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. In: FASEB Journal. 2016 ; Vol. 30, No. 3. pp. 1087-1095.
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AU - Chang, Min Lee

AU - Gu, Yumei

AU - Duncan, Melinda K.

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AB - 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.

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