RGD Reference Report - Endothelial Cdkn1a (p21) overexpression and accelerated senescence in a mouse model of Fuchs endothelial corneal dystrophy. - Rat Genome Database

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Endothelial Cdkn1a (p21) overexpression and accelerated senescence in a mouse model of Fuchs endothelial corneal dystrophy.

Authors: Matthaei, M  Meng, H  Meeker, AK  Eberhart, CG  Jun, AS 
Citation: Matthaei M, etal., Invest Ophthalmol Vis Sci. 2012 Sep 28;53(10):6718-27.
RGD ID: 8661808
Pubmed: PMID:22956607   (View Abstract at PubMed)
PMCID: PMC3462481   (View Article at PubMed Central)
DOI: DOI:10.1167/iovs.12-9669   (Journal Full-text)

PURPOSE: Stress of the endoplasmic reticulum and oxidative stress play critical roles in the pathogenesis of Fuchs Endothelial Corneal Dystrophy (FECD). In the normal aging cornea, cellular stress has been associated with a loss in proliferative capacity (premature senescence) of corneal endothelial cells (CECs). The present study used a transgenic Col8a2(Q455K/Q455K) knock-in mouse model of early-onset FECD to identify the endothelial expression profile of specific cellular stress response-related targets, which may be relevant to late-onset FECD. METHODS: The differential endothelial mRNA levels of cellular stress response-related genes were determined in 12-month-old homozygous Col8a2(Q455K/Q455K) mutant and wild-type mice using customized PCR arrays. Result validation and analysis of additional senescence-related transcripts was performed by real-time PCR. Expression of p53 and p21 was assessed by immunofluorescence. Senescence-associated beta-galactosidase (SA-beta-Gal) activity was investigated by histochemical labeling. Human FECD samples and normal controls were examined for p21 expression by immunohistochemistry. RESULTS: PCR-array analysis showed greater than 2-fold and/or significantly altered endothelial regulation of 19 cellular stress response-related transcripts in Col8a2(Q455K/Q455K) mutant mice; real-time PCR documented statistically significant upregulation of senescence-associated targets Cdkn1a (p21), Serpine1 (PAI-1), Tagln (Sm22), Fn1 and Clu (ApoJ). Immunofluorescence revealed increased expression of nuclear p53 and p21 in mutant animals. SA-beta-Gal staining detected increased proportions of senescent CECs in mutant mice. Human FECD endothelium exhibited increased levels of nuclear p21 protein. CONCLUSIONS: Our results identify endothelial Cdkn1a (p21) upregulation in a mouse model of early-onset FECD, confirm overexpression of p21 in late-onset human FECD endothelium, and suggest a role for premature senescence in FECD.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CDKN1AHumanFuchs' endothelial dystrophy  ISOCdkn1a (Mus musculus)mRNA more ...RGD 
CDKN1AHumanFuchs' endothelial dystrophy  IEP protein:increased expression:nucleus:RGD 
CLUHumanFuchs' endothelial dystrophy  ISOClu (Mus musculus) RGD 
Cdkn1aRatFuchs' endothelial dystrophy  ISOCdkn1a (Mus musculus)mRNA more ...RGD 
Cdkn1aMouseFuchs' endothelial dystrophy  IEP mRNA more ...RGD 
Cdkn1aMouseFuchs' endothelial dystrophy  ISOCDKN1A (Homo sapiens)protein:increased expression:nucleus:RGD 
Cdkn1aRatFuchs' endothelial dystrophy  ISOCDKN1A (Homo sapiens)protein:increased expression:nucleus:RGD 
CluRatFuchs' endothelial dystrophy  ISOClu (Mus musculus) RGD 
CluMouseFuchs' endothelial dystrophy  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cdkn1a  (cyclin-dependent kinase inhibitor 1A)
Clu  (clusterin)

Genes (Mus musculus)
Cdkn1a  (cyclin dependent kinase inhibitor 1A)
Clu  (clusterin)

Genes (Homo sapiens)
CDKN1A  (cyclin dependent kinase inhibitor 1A)
CLU  (clusterin)

Objects referenced in this article
Gene NF2 NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor Homo sapiens
Gene Nf2 neurofibromin 2 Mus musculus
Gene Nf2 NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor Rattus norvegicus

Additional Information