p53 Directly Regulates αA- and βA3/A1-Crystallin Genes to Modulate Lens Differentiation

Abstract

It is well established that the tumor suppressor p53 plays major roles in regulating apoptosis and cell cycle progression. In addition, recent studies have demonstrated that p53 is actively involved in regulating cell differentiation in muscle, the circulatory system and various carcinoma tissues. We have recently shown that p53 also controls lens differentiation. Regarding the mechanism, we reveal that p53 directly regulates c-Maf and Prox1, two important transcription factors to control cell differentiation in the ocular lens. In the present study, we present further evidence to show that p53 can regulate lens differentiation by controlling expression of the differentiation genes coding for the lens crystallins. First, the αA and βA3/A1 gene promoters or introns all contain putative p53 binding sites. Second, gel mobility shifting assays revealed that the p53 protein in nuclear extracts from lens epithelial cells directly binds to the p53 binding sites found in these crystallin gene promoters or introns. Third, exogenous wild type p53 induces dose-dependent expression of the luciferase reporter gene driven by different crystallin gene promoters and the exogenous dominant negative mutant p53 causes dose-dependent inhibition of the same crystallin genes. Fourth, ChIP assays revealed that p53 binds to crystallin gene promoters in vivo. Finally, in the p53 knockout mouse lenses, expression levels of various crystallins were found down-regulated in comparison with those from the wild type mouse lenses. Together, our results reveal that p53 directly regulates expression of different sets of genes to control lens differentiation.

HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators

“… 26 Second, it directly regulates the differentiation-related genes including members of the α -, β - and γ -crystallin genes. 49 , 50 , 58 The promoted expression of β - and γ -crystallin genes are symbols of lens differentiation, thus helping cell maturation in lens fiber. In addition, p53 can regulate a large of number apoptosis regulators.…”

“… 22 At the molecular level, p53 has been shown to regulate both major lens transcription factors c-Maf, Prox-1 26 and differentiation-related crystalline genes. 49 , 50 In addition, p53 regulates numerous apoptotic genes, some of which are implicated in regulating lens differentiation. For example, Fas and Bax mediate both extrinsic and intrinsic death pathways, which are merged to activate the downstream executional caspase3.…”

Study of Association between Pre-Senile Cataracts and the Polymorphisms rs2228000 in XPC and rs1042522 in p53 in Spanish Population

“…Several studies have related this polymorphism with ophthalmological diseases such as retinal vitreous proliferation following retinal detachment [ 46 ] or with glaucoma [ 47 , 48 ]. Ji et al determined that p53 regulates αA- and βA3 / A1–crystallin genes to modulate cell differentiation genes in lens [ 49 ]. We have not found any articles about the association of this polymorphism and cataracts development.…”

Expression of miR‑34a in cataract rats and its related mechanism

“…P53 is a transcription factor whose main function is to regulate the cell life cycle by controlling the expression of multiple genes, thus promoting apoptosis (18,19). Ji et al (20) found that P53 could regulate the cellular differentiation genes in the lens by regulating αA-and βA3/a1-crystallin genes. Therefore, both SIRT1 and P53 can be used as indicators for cataract detection.…”