Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caspases are important for apoptosis but are also involved in mammalian cell survival and cell division. Here we report that caspase-3 is a negative regulator of B cell cycling. Mice deficient in caspase-3 (Casp3-/- mice) have increased numbers of splenic B cells that show normal apoptosis but enhanced proliferation in vivo and hyperproliferation after mitogenic stimulation in vitro. Cdkn1a encodes p21 (also called Waf1 or Cip1), a cyclin-dependent kinase (CDK) inhibitor. Although expression of p21 was increased, CDK activities and proliferating cell nuclear antigen (PCNA) were increased in Casp3-/- B cells. Using Casp3-/-Cdkn1a-/- mice, we show that the hyperproliferation of Casp3-/- B cells is abolished when Cdkn1a is also deleted. Our genetic and biochemical data demonstrate that caspase-3 is essential in the regulation of B cell homeostasis.
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PMID:Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. 1297 Jul 60

Recently, we observed that dietary feeding of silibinin strongly prevents and inhibits the growth of advanced human prostate tumor xenografts in athymic nude mice without any apparent signs of toxicity together with increased secretion of insulin-like growth factor-binding protein 3 from the tumor in to mouse plasma (R. P. Singh et al., Cancer Res., 62:3063-3069, 2002). In the present study, we investigated the effect of silibinin feeding [0.05% and 0.1% (w/w) in diet for 60 days] on the prognostic biomarkers (namely, proliferation, apoptosis, and angiogenesis) in the prostate tumor xenografts of the above-reported study. Immunohistochemical analysis of the tumors for proliferating cell nuclear antigen and Ki-67 showed that silibinin decreases proliferation index by 28-60% and 30-60% (P<0.001) as compared with their controls, respectively. In situ detection of apoptosis by terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling staining of tumors showed a 7.4-8.1-fold (P<0.001) increase in apoptotic cells in silibinin-fed groups over that of control group. Silibinin also increased activated caspase 3-positive cells by 2.3-3.6-fold (P<0.001). CD31 staining for tumor vasculature showed a significant decrease (21-38%; P<0.001) in tumor microvessel density in silibinin-fed groups of tumors as compared with control group of tumors. Tumor sections were also analyzed for vascular endothelial growth factor and insulin-like growth factor-binding protein 3 protein expression, and a slightly decreased and a moderately increased cytoplasmic immunostaining in silibinin-fed groups were observed as compared with the control group, respectively. Together, these results suggest that inhibition of advanced human prostate tumor xenograft growth in athymic nude mice by silibinin is associated with its in vivo antiproliferative, proapoptotic, and antiangiogenic efficacy in prostate tumor.
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PMID:Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. 1450 8

Age-related sarcopenia could partly result from cumulative repeated episodes of incomplete repair and regeneration. We hypothesized that mitotic and metabolic events associated with satellite cell activation and proliferation could be altered with aging. Muscle-derived cells (mdc) were isolated from gastrocnemius and quadriceps muscles of young (3 wk old), adult (9 mo old), and old (24 mo old) Sprague-Dawley male rats (n = 10/group). The mdc from young growing rats started to proliferate earlier compared with adult and old animals. Cell cycle duration was significantly reduced with aging from 36.5 +/- 3.2 to 28.0 +/- 2.2 h. However, the proportion of noncycling (G0 phase) and cycling (G1 + S + G2 + M phases) cultured mdc was statistically unchanged among the three age groups. Significantly lower increase in c-met and proliferating cell nuclear antigen expression were observed in cultured mdc of old rats upon serum stimulation. Major changes in the expression of citrate synthase, lactate dehydrogenase, proteasome, caspase 3, plasminogen activators (PAs), and matrix metalloproteinase 2-9 (MMP2-9) were observed upon serum stimulation, but no age-related difference was noted. However, when measured on crushed muscle extracts, PAs and MMP2-9 enzyme activities were significantly decreased with aging. Our results show that cellular and biochemical events associated with the control of mdc activation and proliferation occur with aging. These alterations may participate in the accumulation of repeated episodes of incomplete repair and regeneration throughout the life span, thus contributing to the loss of skeletal muscle mass and function with aging.
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PMID:Age-related changes in the mitotic and metabolic characteristics of muscle-derived cells. 1455 72

We have investigated the expression of P2X5, P2X7, P2Y1, and P2Y2 receptor subtypes in 8- to 11-wk-old human fetal epidermis in relation to markers of proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67), keratinocyte differentiation (cytokeratin K10 and involucrin), and markers of apoptosis (TdT-mediated dUTP nick end labeling (TUNEL) and anti-caspase-3). Immunohistochemistry showed that each of the four receptors was expressed in spatially distinct zones of the developing epidermis: P2Y1 receptors were found in the basal layer, P2X5 receptors were predominantly in the basal and intermediate layers, and both P2Y2 and P2X7 receptors were in the periderm. Colocalization experiments suggested different functional roles for these receptors. P2Y1 receptors were found in fetal keratinocytes positive for PCNA and Ki-67, suggesting a role in proliferation. P2X5 receptors double labeled with differentiated fetal keratinocytes that were positive for cytokeratin K10, suggesting a role in differentiation. P2X7 receptors colocalized with anti-caspase-3 antibody and were also expressed in periderm cells positive for TUNEL, suggesting a role in periderm cell apoptosis. P2Y2 receptors were found only in periderm cells and may have a role in chloride and fluid secretion into the amniotic fluid.
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PMID:Purinergic receptors are part of a signaling system for keratinocyte proliferation, differentiation, and apoptosis in human fetal epidermis. 1470 18

Higher cyclooxygenase-2 (COX-2) expression is clinically associated with more aggressive gliomas and is a strong predictor of poor survival. To determine whether oral administration of a COX-2-specific inhibitor can inhibit glial tumors, we analyzed the effect of celecoxib on the growth of 9L rat gliosarcoma cells that were orthotopically transplanted into rat brains. Oral administration of celecoxib beginning 1 day after implantation of 5 x 10(4) 9L rat gliosarcoma cells into rat brain reduced the incidence and size of tumors significantly. Immunohistochemical analysis of implanted gliosarcoma cells from rats treated with celecoxib showed lower levels of phospho-Akt, phospho-EGFR, Bcl-2, and Bcl-XL expression compared with untreated tumor cells. Gliosarcoma cells from treated rats had significantly more TUNEL- and caspase-3-positive cells and fewer PCNA-positive cells. These results demonstrate that selective COX-2 inhibitors may be useful as adjuvants and/or therapeutic agents to treat gliomas overexpressing COX-2.
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PMID:Intracranial inhibition of glioma cell growth by cyclooxygenase-2 inhibitor celecoxib. 1471 52

Hepatic stellate cells are the major source of the extracellular matrix that accumulates in fibrotic liver. During progressive liver fibrosis, hepatic stellate cells proliferate, but during resolution of fibrosis there is extensive stellate cell apoptosis that coincides with degradation of the liver scar. We have examined the possibility that the fate of stellate cells is influenced by the extracellular matrix through the intermediary of alpha(v)beta(3) integrin. alpha(v)beta(3) integrin was expressed by activated, myofibroblastic rat and human stellate cells in culture. Antagonism of this integrin using neutralizing antibodies, echistatin, or small inhibitory RNA to silence alpha(v) subunit expression inhibited stellate cell proliferation and their expression of proliferating cell nuclear antigen and activated forms of p44 and p42 MAPK. These alpha(v)beta(3) antagonists also increased apoptosis of cultured stellate cells, and this was associated with an increase in the BAX/BCL-2 protein ratio, induction of nuclear DNA fragmentation, and activation of intracellular caspase-3. Expression of tissue inhibitor of metalloproteinases-1 by activated stellate cells was reduced by the alpha(v)beta(3) antagonists, while matrix metalloproteinase-9 synthesis was enhanced. Stellate cells incubated with active recombinant matrix metalloproteinase-9 showed enhanced apoptosis, while cells treated with a synthetic inhibitor of this protease showed increased survival. Our studies suggest that alpha(v)beta(3) integrin regulates the fate of hepatic stellate cells. Degradation of alpha(v)beta(3) ligands surrounding activated stellate cells during resolution of liver fibrosis might decrease alpha(v)beta(3) integrin ligation, suppressing stellate cell proliferation and inducing a fibrolytic, matrix metalloproteinase-secreting phenotype that may prime stellate cells for apoptosis.
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PMID:Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. 1504 41

Lycopene, an acyclic hydrocarbon carotenoid found in tomatoes and their products, is a well-established potent antioxidant, and its anticancer properties have been shown in cultured cells and animal models. We investigated the protective effects of two concentrations of topical lycopene against acute ultraviolet B (UVB)-induced photodamage. Application of lycopene dose dependently inhibited UVB-induced ornithine decarboxylase (P < 0.05) and myeloperoxidase (P < 0.05) and significantly reduced bifold skin thickness (P < 0.05). Immunohistochemical staining revealed increased active caspase-3 of apoptotic pathway in the UVB-exposed group compared with the unexposed control. Application of topical lycopene prevented the cleavage of caspase-3. UVB irradiation completely diminished proliferating cell nuclear antigen (PCNA), and the untreated skin maintained positively stained cells throughout the basal epidermis. Topical application of lycopene significantly reversed UVB-induced PCNA inhibition, and normal PCNA staining was restored in the lycopene-treated skin. Our results suggest that topical lycopene is able to exert its protective effects against acute UVB-induced photodamage. Furthermore, it may act as a preventative agent via inhibition of epidermal ornithine decarboxylase activity, reducing inflammatory responses, maintaining normal cell proliferation, and possibly preventing DNA damage as indicated by blocking the necessitating step of apoptosis following UVB injury.
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PMID:Protective effects of lycopene against ultraviolet B-induced photodamage. 1508 71

During gestation, the balance between cell proliferation and death is crucial for successful embryo implantation and maintenance of pregnancy. The uterine endometrium responds to blastocyst implantation with extensive proliferation and differentiation of stromal cells into decidual cells, forming the antimesometrial and mesometrial decidua, which regress by apoptosis. In the latter region it is also observed the growth of metrial gland. To elucidate the events underlying this tissue remodelling we investigated the spatial and temporal pattern of expression of the proliferating cell nuclear antigen (PCNA) and localized the apoptotic cells, by the TUNEL assay and by the expression of active caspase-3. We found that PCNA is expressed at high levels during decidualization until day 12 of gestation declining thereafter abruptly. On the contrary, the appearance of apoptotic cells was detected, by the TUNEL and active caspase-3 expression, in the mesometrial decidua on day 12, increasing from days 14 to 16 in the decidua and metrial gland. In the antimesometrial decidua apoptosis was observed from early to day 12 of pregnancy. However, on day 13 only cell debris and neutrophils were observed, indicating also the presence of necrosis. These results suggest that decidual cells undergo, in distinct regions and at different stages of pregnancy, cell death by apoptosis and secondary necrosis.
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PMID:Patterns of uterine cellular proliferation and apoptosis in the implantation site of the rat during pregnancy. 1513 37

To test the hypothesis that VEGF is important for the maintenance of alveolar structure and elastic properties in adult mice, lung-targeted ablation of the VEGF gene was accomplished through intratracheal delivery of an adeno-associated cre recombinase virus (AAV/Cre) to VEGFloxP mice, and the effects were followed for 8 wk. Control mice were similarly treated with AAV/Cre. Pulmonary VEGF levels were reduced by 86% at 5 wk postinfection but returned to normal levels by 8 wk. VEGF receptor VEGFR-2 levels were also reduced at 5 wk (by 51%) and returned to control values by 8 wk. However, alveolar septal wall destruction (increased mean linear intercept) and loss of lung elastic recoil (increased compliance) persisted for 8 wk. No decrease in alveolar cell proliferation was detected by Western blot or immunohistochemical analysis of proliferating cell nuclear antigen. Increased alveolar septal cell and bronchial epithelial cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis at 5 wk. Total lung caspase-3 levels and enzyme activity were also increased at 5 wk. No obvious accumulation of inflammatory cells was observed at any time after tracheal instillation of AAV/Cre. Thus a transient decrease in pulmonary VEGF leads to increased alveolar and bronchial cell apoptosis, air space enlargement, and changes in lung elastic recoil (processes that are characteristic of emphysema) that persist for at least 8 wk.
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PMID:Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice. 1520 95

Here, we assessed the protective effect of silibinin on UVB-induced skin carcinogenesis in SKH-1 hairless mice. Topical application of silibinin before or immediately after UVB exposure or its dietary feeding resulted in a strong protection against photocarcinogenesis, in terms of tumor multiplicity (60-66%; P < 0.001), tumor volume per mouse (93-97%; P < 0.001) and tumor volume per tumor (80-91%; P < 0.001). Silibinin also moderately inhibited tumor incidence (5-15%; P < 0.01) and delayed tumor latency period (up to 4 weeks; P < 0.01-0.001). To investigate in vivo molecular mechanisms of silibinin efficacy, tumors and uninvolved skin from tumor-bearing mice were examined immunohistochemically for proliferation, p53, apoptosis, and activated caspase-3. Silibinin treatment showed a strong decrease (P < 0.001) in proliferating cell nuclear antigen-positive cells and an increase in p53-positive (P < 0.005-0.001), terminal deoxynucleotidyltransferase-mediated nick end labeling-positive (P < 0.005-0.001), and cleaved caspase-3-positive cells (P < 0.001). Western blot analysis of normal skin and tumor lysates showed that silibinin decreases the levels of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 and associated cyclins A, E, and D1, together with an up-regulation of Cip1/p21, Kip1/p27, and p53. Silibinin also showed a strong phosphorylation of extracellular signal-regulated protein kinase 1/2, stress-activated protein kinase/c-JUN NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinases but inhibited Akt phosphorylation and decreased survivin levels with an increase in cleaved caspase-3. Together, these results show a strong preventive efficacy of silibinin against photocarcinogenesis, which involves the inhibition of DNA synthesis, cell proliferation, and cell cycle progression and an induction of apoptosis. Furthermore, these results also identify in vivo molecular mechanisms of silibinin efficacy against photocarcinogenesis.
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PMID:Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and Akt signaling. 1534 25


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