Deficiency of heat shock factor 4 promotes lens epithelial cell senescence through upregulating p21cip1 expression

Cui, Xiukun; Du, Chunxiao; Wan, Simin; Wu, Dandan; Yan, Longjun; Zhang, Jing; Li, Jing; Li, Hui; Yang, Zhengyan; Zhang, Hailong; Zhang, Jun; Mu, Hongmei; Zhang, Fengyan; Peng, Xuyan; Liu, Mugen; Hu, Yanzhong

doi:10.1016/j.bbadis.2021.166233

Cited by 11 publications

(13 citation statements)

References 40 publications

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“…The levels of numerous genes required for proteolysis and cytoskeleton formation were triggered in the miR‐184 −/− eyes compared with the WT eyes (Figure 7D). It is suggested that transcription factors HSF4, Sox9a, CTCF, and Smad6a could suppress the expression of p21 33,43–45 . Then, the levels of four transcription factors were further validated and our data indicated that all the mRNA levels of hsf4, sox9a, ctcf, and smad6a were decreased in miR‐184 −/− eyes (Figure 7E–H).…”

Section: Resultsmentioning

confidence: 72%

“…The pellets were dissolved in the sample loading buffer containing 1% SDS and 1.3 M 2‐mercaptoethanol and designated the SDS‐insoluble fraction. Western blotting was performed as described previously 33 . The α‐crystallin (#sc‐28 306), γ‐crystallin (#sc‐22 746) antibodies was purchased from Santa Cruz.…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was performed as described previously. 33 The αcrystallin (#sc-28 306), γcrystallin (#sc-22 746) antibodies was purchased from Santa Cruz. The βcrystallin antibody (#18154-1-AP) was ordered from Proteintech, while the βactin (#A5441) antibody was from Sigma.…”

Section: Fractionation Of Lens Lysates and Western Blottingmentioning

confidence: 99%

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Knockout of miR‐184 in zebrafish leads to ocular abnormalities by elevating p21 levels

Zhang

Sun

et al. 2023

The FASEB Journal

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miR‐184 is one of the most abundant miRNAs expressed in the lens and corneal tissue. Mutations in the seed region of miR‐184 are responsible for inherited anterior segment dysgenesis. Animal models recapitulating miR‐184‐related anterior segment dysgenesis are still lacking, and the molecular basis of ocular abnormalities caused by miR‐184 dysfunction has not been well elucidated in vivo. In the present study, we constructed a miR‐184−/− zebrafish line by destroying both two dre‐mir‐184 paralogs with CRISPR‐Cas9 technology. Although there were no gross developmental defects, the miR‐184−/− zebrafish displayed microphthalmia and cataract phenotypes. Cytoskeletal abnormalities, aggregation of γ‐crystallin, and lens fibrosis were induced in miR‐184−/− lenses. However, no obvious corneal abnormalities were observed in miR‐184−/− zebrafish. Instead of apoptosis, deficiency of miR‐184 led to aberrant cell proliferation and a robust increase in p21 levels in zebrafish eyes. Inhibition of p21 by UC2288 compromised the elevation of lens fibrosis markers in miR‐184−/− lenses. RNA‐seq demonstrated that levels of four transcriptional factors HSF4, Sox9a, CTCF, and Smad6a, all of which could suppress p21 expression, were reduced in miR‐184−/− eyes. The predicted zebrafish miR‐184 direct target genes (e.g., atp1a3a and nck2a) were identified and verified in miR‐184−/− eye tissues. The miR‐184−/− zebrafish is the first animal model mimicking miR‐184‐related anterior segment dysgenesis and could broaden our understanding of the roles of miR‐184 in eye development.

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Section: Resultsmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

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Knockout of miR‐184 in zebrafish leads to ocular abnormalities by elevating p21 levels

Zhang

Sun

et al. 2023

The FASEB Journal

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“…This indicates increased senescence of LECs in lenses with D-galactose-induced cataracts. In addition to the D-galactose-induced cataract model, other congenital cataract models also show increased senescence of LECs, such as heat shock 4-deficient mice and vimentin-deficient mice [ 23 , 24 ]. Moreover, several population-based studies have reported that LEC senescence is significantly increased in cataract lenses [ 5 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

Reduction in Lens Epithelial Cell Senescence Burden through Dasatinib Plus Quercetin or Rapamycin Alleviates D-Galactose-Induced Cataract Progression

Wang

Tseng

Chen

et al. 2022

JFB

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Senescent cells accumulate in aged organisms and promote the progression of age-related diseases including cataracts. Therefore, we aimed to study the therapeutic effects of senescence-targeting drugs on cataracts. In this study, a 28-day D-galactose-induced cataract rat model was used. The opacity index, a grading based on slit-lamp observations, was used to assess lens cloudiness. Furthermore, the average lens density (ALD), lens density standard deviation (LDSD), and maximum lens density (MLD) obtained from Scheimpflug images were used to assess lens transparency. Immunohistochemical stainings for p16 and γH2AX were used as hallmarks of senescence. We treated rat cataract models with the senolytic drug combination dasatinib plus quercetin (D+Q) and senescence-associated secretory phenotype (SASP) inhibitors. In comparison to control lenses, D-galactose-induced cataract lenses showed a higher opacity index, ALD, LDSD, and MLD values, as well as accumulation of senescent lens epithelial cells (LECs). After D+Q treatment, ALD, LDSD, and MLD values on day 21 were significantly lower than those of vehicle-treated model rats. The expression levels of p16 and γH2AX were also reduced after D+Q administration. In addition, the SASP inhibitor rapamycin decreased the opacity index, ALD, LDSD, and MLD values on day 21. In conclusion, D+Q alleviated D-galactose-induced cataract progression by reducing the senescent LEC burden in the early stage of cataract.

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“…[14][15][16] In addition to the morphological change to fiber cells and down-expression of E-cadherin, differentiation of lens epithelial cells activates the expression of cell cycle inhibitors (such as p27kip1 and p57kip2) as well as fiber cell specific proteins including alpha-, beta-, and gamma-crystallins, aqueous channel proteins (MIP26), and the intermediate filaments (BSFP1, CP49). 17,18 This differentiation process is predominantly regulated by a stepwise activation of distinct transcriptional factors (such as Pax6, Sox2, Sitx 2, Prox1, c-MAF, and HSF4) 16,[19][20][21] as well as growth factors (e.g., FGF2, BMP, TGF-β et al). 5,11,22 After cataract surgery, the residual lens epithelial cells are exposed to a myriad of growth factors.…”

Section: Introductionmentioning

confidence: 99%

Extracellular HSP90 promotes differentiation of lens epithelial cells to fiber cells by activating LRP1‐YAP‐PROX1 axis

Huang

et al. 2023

The FASEB Journal

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Capsular residual lens epithelial cells (CRLEC) undergo differentiation to fiber cells for lens regeneration or tansdifferentiation to myofibroblasts leading to posterior capsular opacification (PCO) after cataract surgery. The underlying regulatory mechanism remains unclear. Using human lens epithelial cell lines and the ex vivo cultured rat lens capsular bag model, we found that the lens epithelial cells secrete HSP90α extracellularly (eHSP90) through an autophagy‐associated pathway. Administration of recombinant GST‐HSP90α protein or its M‐domain induces the elongation of rat CRLEC cells with concomitant upregulation of the crucial fiber cell transcriptional factor PROX1and its downstream targets, β‐ and γ‐crystallins and structure proteins. This regulation is abolished by PROX1 siRNA. GST‐HSP90α upregulates PROX1 by binding to LRP1 and activating LRP1‐AKT mediated YAP degradation. The upregulation of GST‐HSP90α on PROX1 expression and CRLEC cell elongation is inhibited by LRP1 and AKT inhibitors, but activated by YAP‐1 inhibitor (VP). These data demonstrated that the capsular residue epithelial cells upregulate and secrete eHSP90α, which in turn drive the differentiation of lens epithelial cell to fiber cells. The recombinant HSP90α protein is a potential novel differentiation regulator during lens regeneration.

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Deficiency of heat shock factor 4 promotes lens epithelial cell senescence through upregulating p21cip1 expression

Cited by 11 publications

References 40 publications

Knockout of miR‐184 in zebrafish leads to ocular abnormalities by elevating p21 levels

Knockout of miR‐184 in zebrafish leads to ocular abnormalities by elevating p21 levels

Reduction in Lens Epithelial Cell Senescence Burden through Dasatinib Plus Quercetin or Rapamycin Alleviates D-Galactose-Induced Cataract Progression

Extracellular HSP90 promotes differentiation of lens epithelial cells to fiber cells by activating LRP1‐YAP‐PROX1 axis

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