Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several families of growth factors have been identified as regulators of cell fate in the developing lens. Members of the fibroblast growth factor family are potent inducers of lens fiber differentiation. Members of the transforming growth factor beta (TGFbeta) family, particularly bone morphogenetic proteins, have also been implicated in various stages of lens and ocular development, including lens induction and lens placode formation. However, at later stages of lens development, TGFbeta family members have been shown to induce pathological changes in lens epithelial cells similar to those seen in forms of human subcapsular cataract. Previous studies have shown that type I and type II TGFbeta receptors, in addition to being expressed in the epithelium, are also expressed in patterns consistent with a role in lens fiber differentiation. In this study we have investigated the consequences of disrupting TGFbeta signaling during lens fiber differentiation by using the mouse alphaA-crystallin promoter to overexpress mutant (kinase deficient), dominant-negative forms of either type I or type II TGFbeta receptors in the lens fibers of transgenic mice. Mice expressing these transgenes had pronounced bilateral nuclear cataracts. The phenotype was characterized by attenuated lens fiber elongation in the cortex and disruption of fiber differentiation, culminating in fiber cell apoptosis and degeneration in the lens nucleus. Inhibition of TGFbeta signaling resulted in altered expression patterns of the fiber-specific proteins, alpha-crystallin, filensin, phakinin and MIP. In addition, in an in vitro assay of cell migration, explanted lens cells from transgenic mice showed impaired migration on laminin and a lack of actin filament assembly, compared with cells from wild-type mice. These results indicate that TGFbeta signaling is a key event during fiber differentiation and is required for completion of terminal differentiation.
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PMID:Requirement for TGFbeta receptor signaling during terminal lens fiber differentiation. 1164 Dec 23

AP-2alpha is a developmentally important transcription factor which has been implicated in the regulation of cell growth, programmed cell death, and differentiation. To investigate the specific function of AP-2alpha in differentiation of the lens, AP-2alpha was expressed in the differentiating lens fiber cells under control of the alphaA-crystallin promoter. Normally, AP-2alpha is selectively expressed in lens epithelial cells and expression terminates at the lens equator, where epithelial cells terminally differentiate into fiber cells. Ectopic expression of the AP-2alpha gene in the fiber cell compartment resulted in bilateral cataracts and microphthalmia in mice by 2 weeks of age. Histological evaluation of embryonic and adult transgenic lenses revealed a significant reduction in lens size and anterior shifting of the transitional zone. Two aspects of fiber cell differentiation were also blocked, including the migration of newly formed fiber cells and an inhibition in fiber cell denucleation. Correlated with these defects were expanded expression of E-cadherin in the lens transitional zone and reduced expression of the fiber cell-specific protein MIP (major intrinsic protein). Together, these data demonstrate that AP-2alpha acts as a negative regulator of terminal fiber cell differentiation through the regulation of genes involved in cell adhesion and migration.
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PMID:Ectopic expression of AP-2alpha transcription factor in the lens disrupts fiber cell differentiation. 1196 52

We have conducted a survey of the expression patterns of five genes encoding three different classes of major lens proteins during eye degeneration in the blind cavefish Astyanax mexicanus. This species consists of two forms, an eyed surface-dwelling form (surface fish) and a blind cave-dwelling (cavefish) form. Cavefish form an optic primordium with a lens vesicle and optic cup. In contrast to surface fish, however, the cavefish lens does not differentiate fiber cells and undergoes massive apoptosis. The genes encoding the lens intrinsic membrane proteins MIP and MP19 and the divergent betaB1- and gammaM2-crystallins are expressed during cavefish lens development, although their levels are reduced because of a smaller lens, and the spatial distribution of their transcripts is modified because of the lack of differentiated fiber cells. In contrast, the alphaA-crystallin gene, which encodes a heat shock protein-related chaperone with antiapoptotic activity, is substantially downregulated in the developing cavefish lens. The results suggest that suppression of alphaA-crystallin antiapoptotic activity may be involved in cavefish eye degeneration.
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PMID:Lens gene expression analysis reveals downregulation of the anti-apoptotic chaperone alphaA-crystallin during cavefish eye degeneration. 1802 50