Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zinc deficiency (ZD) in rats increases esophageal cell proliferation and the incidence of N-nitrosomethylbenzylamine-induced esophageal tumors. Conversely, zinc replenishment (ZR) rapidly induces apoptosis in esophageal epithelia and reverses cancer development. We investigated gene expression changes in ZR versus ZD esophageal epithelia to identify differentially expressed genes associated with the antitumor effect of ZR. Weanling rats were fed a ZD diet for 6 weeks to establish esophageal cell proliferation or a zinc-sufficient (ZS) diet. Then, 10 ZD rats were treated with zinc gluconate intragastrically and switched to ZS diet; the remaining 10 ZD and ZS animals were treated with saline. All animals were killed 26-28 h later. Using cDNA microarrays, real-time polymerase chain reaction amplification and RNA hybridization techniques, we identified novel differentially expressed genes, including a RNA-binding protein with two RNA recognition motifs and a zinc knuckle (ZD7), and a DNA/RNA helicase with a DEAD box (ZD10) with two splice variants, ZD10a and ZD10b. In situ hybridization detected increased mRNA expression of ZD7, ZD10a and ZD10b in ZR esophageal epithelia, which displayed markedly increased occurrence of apoptotic cells, relative to ZD epithelia. Overexpression of ZD7 in human esophageal cancer cells resulted in induction of apoptosis and activation of caspase-3 and -7, activities that were inhibited by caspase-specific inhibitors. In addition, ZD7 mRNA levels and zinc-induced apoptosis in rat squamous carcinoma cells were reduced by specific small interfering ribonucleic acids. Thus, ZR rapidly induces ZD7 and ZD10 expression, which in turn stimulates apoptosis. These results provide the beginnings of a molecular pathway for zinc-induced apoptosis under conditions that reverse esophageal tumor initiation.
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PMID:Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats. 1536 27

The trace element zinc is essential for the survival and function of all cells. Zinc deficiency, whether nutritional or genetic, is fatal if left untreated. The effects of zinc deficiency are particularly obvious in the skin, seen as an erythematous rash, scaly plaques, and ulcers. Electron microscopy reveals degenerative changes within keratinocytes. Despite the well-documented association between zinc deficiency and skin pathology, it is not clear which cellular processes are most sensitive to zinc deficiency and could account for the typical pathological features. We used the cultured HaCaT keratinocyte line to obtain insight into the cellular effects of zinc deficiency, as these cells show many characteristics of normal skin keratinocytes. Zinc deficiency was induced by growing cells in the presence of the zinc chelator, TPEN, or by growth in zinc-deficient medium. Growth of cells in zinc-deficient medium resulted in a 44% reduction of intracellular zinc levels and a 75% reduction in the activity of the zinc-dependent enzyme, 5'-nucleotidase, relative to the control cells. Over a period of 7 days of exposure to zinc-deficient conditions, no changes in cell viability and growth, or in the cytoskeletal and cell adhesion systems, were found in HaCaT cells. At 7 days, however, induction of apoptosis was indicated by the presence of DNA fragmentation and expression of active caspase-3 in cells. These results demonstrate that apoptosis is the earliest detectable cellular change induced by zinc deficiency in HaCaT keratinocytes. Our observations account for many of the features of zinc deficiency, including the presence of degenerate nuclei, chromatin aggregates and abnormal organization of keratin, that may represent the later stages of apoptosis. In summary, a major causal role for apoptosis in the pathology of zinc deficiency in the skin is proposed. This role is consistent with the previously unexplained diverse range of degenerative cellular changes seen at the ultrastructural level in zinc-deficient keratinocytes.
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PMID:Apoptosis may underlie the pathology of zinc-deficient skin. 1640 50

Zinc is essential for normal brain development. Gestational severe zinc deficiency can lead to overt fetal brain malformations. Although not teratogenic, suboptimal zinc nutrition during gestation can have long-term effects on the offspring's nervous system. This article will review current knowledge on the role of zinc in modulating neurogenesis and neuronal apoptosis as well as the proposed underlying mechanisms. A decrease in neuronal zinc causes cell cycle arrest, which in part involves a deregulation of select signals (ERK1/2, p53, and NF-kappaB). Zinc deficiency also induces apoptotic neuronal death through the intrinsic (mitochondrial) pathway, which can be triggered by the activation of the zinc-regulated enzyme caspase-3, and as a consequence of abnormal regulation of prosurvival signals (ERK1/2 and NF-kappaB). Alterations in the finely tuned processes of neurogenesis, neuronal migration, differentiation, and apoptosis, which involve the developmental shaping of the nervous system, could have a long-term impact on brain health. Zinc deficiency during gestation, even at the marginal levels observed in human populations, could increase the risk for behavioral/neurological disorders in infancy, adolescence, and adulthood.
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PMID:Zinc deficiency and neurodevelopment: the case of neurons. 2033 53

Zinc deficiency causes skin diseases both in humans and in animals. The underlying pathogenic mechanisms remain unclear, but a growing body of evidence indicates a role for zinc in skin protection against free radical-induced oxidative damage. The immunohistochemical expression of heat shock proteins (HSPs; Hsp27, Hsp72, Hsp73 and Hsp90), Cu/Zn superoxide dismutase (SOD), metallothionein (MT), Ki-67 antigen and active caspase-3 were evaluated in normal canine skin and in samples from eight dogs with zinc-responsive dermatosis. All investigated HSPs showed intense cytoplasmic immunostaining in the affected epidermis. Focal nuclear positivity of Hsp72 was also detected in keratinocytes. Although Cu/Zn SOD expression was similar to that observed in normal skin, MT immunoreactivity occurred in both the cytoplasm and the nucleus of basal cells in normal skin but was absent from the affected epidermis. Caspase-3 activation was also absent in the involved epidermis, which revealed a high Ki-67 index (a 3.5- to 9-fold increase compared with normal skin). These results support the hypothesis that cellular response to stress, particularly oxidative stress, is involved in the pathogenesis of skin lesions in canine zinc-responsive dermatosis. The lack of MT immunoreactivity in the affected epidermis may be indicative of low zinc levels, thus resulting in vulnerability to oxidative damage. In contrast, high expression levels of HSPs in skin during zinc deficiency may confer protection against a variety of dangerous stimuli, contributing to inhibition of apoptosis and to cell cycle regulation of proliferating keratinocytes.
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PMID:Oxidative stress in the pathogenesis of canine zinc-responsive dermatosis. 2072 88

Integrity of the airway epithelium (AE) is important in the context of inhaled allergens and noxious substances, particularly during asthma-related airway inflammation where there is increased vulnerability of the AE to cell death. Apoptosis involves a number of signaling pathways which activate procaspases leading to cleavage of critical substrates. Understanding the factors which regulate AE caspases is important for development of strategies to minimize AE damage and airway inflammation, and therefore to better control asthma. One such factor is the essential dietary metal zinc. Zinc deficiency results in enhanced AE apoptosis, and worsened airway inflammation. This has implications for asthma, where abnormalities in zinc homeostasis have been observed. Zinc is thought to suppress the steps involved in caspase-3 activation. One target of zinc is the family of inhibitor of apoptosis proteins (IAPs) which are endogenous regulators of caspases. More studies are needed to identify the roles of IAPs in regulating apoptosis in normal and inflamed airways and to study their interaction with labile zinc ions. This new information will provide a framework for future clinical studies aimed at monitoring and management of airway zinc levels as well as minimising airway damage and inflammation in asthma.
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PMID:Zinc-rich inhibitor of apoptosis proteins (IAPs) as regulatory factors in the epithelium of normal and inflamed airways. 2346 81

The intestinal epithelium is a renewable tissue that requires precise balance between proliferation and differentiation, an essential process for the formation of a tightly sealed barrier. Zinc deficiency impairs the integrity of the intestinal epithelial barrier and is associated with ulcerative and diarrheal pathologies, but the mechanisms underlying the role of Zn(2+) are not well understood. Here, we determined a role of the colonocytic Zn(2+) sensing receptor, ZnR/GPR39, in mediating Zn(2+)-dependent signaling and regulating the proliferation and differentiation of colonocytes. Silencing of ZnR/GPR39 expression attenuated Zn(2+)-dependent activation of ERK1/2 and AKT as well as downstream activation of mTOR/p70S6K, pathways that are linked with proliferation. Consistently, ZnR/GPR39 silencing inhibited HT29 and Caco-2 colonocyte proliferation, while not inducing caspase-3 cleavage. Remarkably, in differentiating HT29 colonocytes, silencing of ZnR/GPR39 expression inhibited alkaline phosphatase activity, a marker of differentiation. Furthermore, Caco-2 colonocytes showed elevated expression of ZnR/GPR39 during differentiation, whereas silencing of ZnR/GPR39 decreased monolayer transepithelial electrical resistance, suggesting compromised barrier formation. Indeed, silencing of ZnR/GPR39 or chelation of Zn(2+) by the cell impermeable chelator CaEDTA was followed by impaired expression of the junctional proteins, that is, occludin, zonula-1 (ZO-1) and E-cadherin. Importantly, colon tissues of GPR39 knockout mice also showed a decrease in expression levels of ZO-1 and occludin compared with wildtype mice. Altogether, our results indicate that ZnR/GPR39 has a dual role in promoting proliferation of colonocytes and in controlling their differentiation. The latter is followed by ZnR/GPR39-dependent expression of tight junctional proteins, thereby leading to formation of a sealed intestinal epithelial barrier. Thus, ZnR/GPR39 may be a therapeutic target for promoting epithelial function and tight junction barrier integrity during ulcerative colon diseases.
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PMID:The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon. 2496 69