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)

Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in either cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Recently we have taken advantage of gadd45a and gadd45b deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. Myeloid enriched BM cells from gadd45a and gadd45b deficient mice were observed to be more sensitive to ultraviolet radiation (UVC), VP-16, and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a and gadd45b deficient cells was evident also by enhanced activation of caspase-3 and PARP cleavage and decreased expression of cIAP-1, Bcl-2, and Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45 deficient BM cells restored the wt apoptotic phenotype. Both gadd45a and gadd45b deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Additional work conducted in this laboratory has shown that in hematopoietic cells exposed to UV radiation gaddd45a and gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the Gadd45a-p38-NF-kB-mediated survival pathway and Gadd45b-mediated inhibition of the stress response MKK4-JNK pathway [O. Kovalsky, F.D. Lung, P.P. Roller, A.J. Fornace, Jr. Oligomerization of human Gadd45a protein. J Biol Chem. 276 (42) (2001) 39330-39339]. These data reveal novel mechanisms that mediate the pro-survival functions of gadd45a and gadd45b in hematopoietic cells following UV irradiation. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs. This knowledge should contribute to a greater understanding of the genetic events involved in the pathogenesis of different leukemias and response of normal and malignant hematopoietic cells to chemo and radiation therapy. These observations set the stage to evaluate, in clinically relevant settings, the impact that the status of gadd45a and gadd45b might have on the efficacy of DNR or VP-16 in killing leukemic cells.
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PMID:Gadd45 in the response of hematopoietic cells to genotoxic stress. 1765 13

We previously reported marked differences in small intestinal morphology, including changes in crypt depth and villous height, after inoculation of germ-free pigs with different bacterial species. In an attempt to identify the mechanisms governing changes in villous morphology associated with bacterial colonization, 2 gnotobiotic experiments were performed. In each experiment, 16 piglets were allocated to 4 treatment groups including germ-free (GF), monoassociation with Lactobacillus fermentum (LF) or Escherichia coli (EC), or conventionalized with sow feces (SF). Piglets were reared under gnotobiotic conditions until 14 d of age, at which time whole intestinal tissue and enterocytes were collected for histological, gene expression, and protein analysis. Proliferating cell nuclear antigen, tumor necrosis factor alpha (TNFalpha), Fas ligand (FasL), CD3epsilon, caspase 3 (casp3), and toll-like receptors (TLR)2, 4, and 9 expression were measured by quantitative PCR. Activated casp3 was measured by Western blot. Increased abundance of activated casp3 and transcripts encoding proliferating cell nuclear antigen, TNFalpha, CD3epsilon, and FasL was observed in SF and EC treatment groups compared with GF and LF. Expression of TLR2 was increased (P < 0.05) in the SF treatment and tended to be greater (P < 0.08) in EC relative to LF and GF. Results indicate that conventional bacteria and E. coli but not L. fermentum increase overall cell turnover by stimulating increased apoptosis through the expression of FasL and TNFalpha and by increasing cell proliferation. The differential regulation of TLR expression indicates that microbially induced changes may be mediated in part by these receptors. Induction of inflammatory responses and activation of apoptosis through death receptors appears to play a significant role in enterocyte turnover mediated by commensal bacteria.
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PMID:Enterocyte proliferation and apoptosis in the caudal small intestine is influenced by the composition of colonizing commensal bacteria in the neonatal gnotobiotic pig. 1778 95

In the adult murine hippocampus, dentate gyrus (DG), neurogenesis and neural cell death are thought to affect learning and memory in incompletely understood mechanism(s). Because cholinergic neurotransmission influences both of these functions, we hypothesized that cholinergic signaling, affected by acetylcholinesterase (AChE) activity, expression level, and alternative splicing, may provide a link between these processes. To challenge this hypothesis, we compared DG neurogenesis in transgenic mice overexpressing engineered "synaptic" AChE-S, incapable of acetylcholine (ACh) hydrolysis (TgSin) with strain-matched controls. In control mice, we observed increasing AChE gene expression with progressing neurogenesis. This involved dividing DG neurons expressing proliferating cell nuclear antigen (PCNA) and Tuj1-positive committed neurons compared with neighboring cells. However, TgSin hippocampi with lower hydrolytic AChE activity showed more PCNA-labeled cells than controls. In contrast, TgS mice overexpressing catalytically active AChE-S, with higher than control levels of AChE hydrolytic activity, presented elevated cell labeling by both bromodeoxyuridine and caspase-3, reflecting facilitated survival of newly born neurons as well as increased neural apoptosis. In comparison, overexpression of the stress-induced "readthrough" AChE-R variant in TgR mice resulted in higher hydrolytic activities but unchanged neurogenesis and apoptosis parameters, while all strains presented similar granule cell layer areas, cell density, and neuron numbers. Importantly, this homeostasis was maintained at a cognitive cost: in the hippocampal-dependent socially transmitted food preference task, TgS and TgSin mice showed impaired acquisition and retention, respectively. Our findings suggest that replacement of AChE-S with AChE-R serves to maintain DG homeostasis and associated cognitive tasks, highlighting the role of cholinergic signaling in adult hippocampal neurogenesis and functioning.
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PMID:Transgenic inactivation of acetylcholinesterase impairs homeostasis in mouse hippocampal granule cells. 1796 Jun 45

The mechanism for the clearance of excess healing fibroblasts at the end of tendon healing has not been reported despite the importance of maintaining tissue homeostasis. This study investigated the role of apoptosis in cell turnover in a rat central 1/3 patellar tendon donor site injury model. At days 4, 7, 14, 28, months 2 and 6, the rats were killed. Patellar tendons without injury served as control. Apoptotic cells were determined by an in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay and anti-active caspase-3 antibodies, while proliferating cells were determined by anti-proliferating cell nuclear antigen antibodies. The total fibroblast-like cell density in the center of the wound increased from day 4 and thereafter steadily returned to normal. In situ TUNEL assay showed few positive staining cells in the wound at days 4 and 7. The percentages of TUNEL-positive fibroblast-like cells showing morphological characteristics of apoptosis increased sharply and reached the maximum on day 28 (median %: 31.38%). No fibroblast-like cell was stained at month 6 and the healed tissue was similar to that in a normal uninjured tendon. A similar trend was observed with active caspase-3 immunohistochemistry. In conclusion, an increase in apoptosis at the end of tendon healing coincided with a decrease in cellularity.
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PMID:Increased apoptosis at the late stage of tendon healing. 1797 Oct 16

We have shown that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, inhibits growth and induces apoptosis in human pancreatic cancer cells. However, the preclinical potential of EGCG in a suitable mouse model has not been examined. In this study, we examined the molecular mechanisms by which EGCG inhibited growth, invasion, metastasis and angiogenesis of human pancreatic cancer cells in a xenograft model system. EGCG inhibited viability, capillary tube formation and migration of HUVEC, and these effects were further enhanced in the presence of an ERK inhibitor. In vivo, AsPC-1 xenografted tumors treated with EGCG showed significant reduction in volume, proliferation (Ki-67 and PCNA staining), angiogenesis (vWF, VEGF and CD31) and metastasis (MMP-2, MMP-7, MMP-9 and MMP-12) and induction in apoptosis (TUNEL), caspase-3 activity and growth arrest (p21/WAF1). EGCG also inhibited circulating endothelial growth factor receptor 2 (VEGF-R2) positive endothelial cells derived from xenografted mice. Tumor samples from EGCG treated mice showed significantly reduced ERK activity, and enhanced p38 and JNK activities. Overall, our data suggest that EGCG inhibits pancreatic cancer growth, invasion, metastasis and angiogenesis, and thus could be used for the management of pancreatic cancer prevention and treatment.
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PMID:EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. 1798 59

Beta,beta-dimethyl acryl shikonin is an extract from the root of plant Arnebia nobilis which has been shown to possess anti-cancer activity. However, its toxicity limited further development of shikonin as a therapeutic agent. Subsequently, several analogues of beta,beta-dimethyl acryl shikonin were synthesized. One of these analogues, shikonin 93/637 was found to be significantly less toxic compared to shikonin. This study is aimed to determine the cell cycle associated differences in the susceptibility of U937 cells to apoptosis induced by shikonin analogue 93/637 (SA). Lower concentrations of SA (approximately 100 nM) showed no significant changes in cell growth. However, higher concentrations (approximately 500 nM) resulted in growth inhibition of U937 cells after 48 h of treatment with SA as measured by MTT assay. Flow cytometric analysis showed that SA treatment resulted in blocking of cell cycle progression in G1 phase. Decreased expression of Cyclin D, CDK 4 and PCNA was observed with SA treatment corroborating the G1 block. DNA gel electrophoresis showed an oligonucleotide ladder pattern, a distinct characteristic of DNA fragmentation associated with programmed cell death. Ribonuclease protection assay revealed inhibition of bcl2 expression at transcriptional level. SA treatment also resulted in induction of caspase-3 activity. The results suggest the involvement of bcl2 and Caspase-3 in SA induced apoptosis of human U937 cells.
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PMID:Shikonin analogue (SA) 93/637 induces apoptosis by activation of caspase-3 in U937 cells. 1798 69

Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats were injected intravenously with lipopolysaccharide (LPS) 24 h after 70% hepatectomy. Glycyrrhizin, pre-administered three times with 24 h intervals 48 h before hepatectomy, prolonged the survival of rats submitted to partial hepatectomy and LPS injection, compared with saline controls. Glycyrrhizin was shown to attenuate histological hepatic changes and significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase, at all the indicated times (6 rats from each were sacrificed 1, 3, 6, and 9 h after LPS injection), compared with saline controls. Glycyrrhizin also significantly inhibited hepatocyte apoptosis by down-regulating the expression of caspase-3 and inhibiting the release of cytochrome C from mitochondria into the cytoplasm. The anti-inflammatory activity of glycyrrhizin may rely on the inhibition of release of tumor necrosis factor-a, myeloperoxidase activity, and translocation of nuclear factor-kappa B into the nuclei. Glycyrrhizin also up-regulated the expression of proliferating cell nuclear antigen, implying that it might be able to promote regeneration of livers harmed by LPS. In summary, glycyrrhizin may represent a potent drug protecting the liver against endotoxin-induced injury, especially after massive hepatectomy.
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PMID:Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats. 1799 67

Protein kinases are critical signalling molecules for normal cell growth and development. CDK11p58 is a p34cdc2-related protein kinase, and plays an important role in normal cell cycle progression. However its distribution and function in the central nervous system (CNS) lesion remain unclear. In this study, we mainly investigated the protein expression and cellular localization of CDK11 during spinal cord injury (SCI). Western blot analysis revealed that CDK11p58 was not detected in normal spinal cord. It gradually increased, reached a peak at 3 day after SCI, and then decreased. The protein expression of CDK11(p58) was further analyzed by immunohistochemistry. The variable immunostaining patterns of CDK11p58 were visualized at different periods of injury. Double immunofluorescence staining showed that CDK11 was co-expressed with NeuN, CNPase and GFAP. Co-localization of CDK11/active caspase-3 and CDK11/proliferating cell nuclear antigen (PCNA) were detected in some cells. Cyclin D3, which was associated with CDK11p58 and could enhance kinase activity, was detected in the normal and injured spinal cord. The cyclin D3 protein underwent a similar pattern with CDK11p58 during SCI. Double immunofluorescence staining indicated that CDK11 co-expressed with cyclin D3 in neurons and glial cells. Coimmunoprecipitation further showed that CDK11p58 and cyclin D3 interacted with each other in the damaged spinal cord. Thus, it is likely CDK11p58 and cyclin D3 could interact with each other after acute SCI. Another partner of CDK11p58 was beta-1,4-galactosyltransferase 1 (beta-1,4-GT 1). The co-localization of CDK11/beta-1,4-GT 1 in the damaged spinal cord was revealed by immunofluorescence analysis. The cyclin D3-CDK4 complexes were also present by coimmunoprecipitation analysis. Taken together, these data suggested that both CDK11 and cyclin D3 may play important roles in spinal cord pathophysiology.
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PMID:Increased expression of CDK11p58 and cyclin D3 following spinal cord injury in rats. 1800 45

Cell proliferation and apoptosis are hormone-dependent physiological processes involved in endometrial growth and regression. The aims of the present study were: (1) to evaluate endometrial cell proliferation using proliferating cell nuclear antigen (PCNA) expression; (2) to evaluate the induction of endometrial cell death by the expression of active caspase-3 and the apoptotic phenotype visualised by DNA fragmentation; and (3) to relate these observations to endometrial tissue dynamics in the equine endometrium throughout the oestrous cycle. Endometria were assigned to follicular and luteal phases based on ovarian structures and plasma progesterone. Cell proliferation and active caspase-3-mediated apoptosis were expressed in both phases of the oestrous cycle. In the luteal phase, PCNA expression was higher than in the follicular phase. Highest PCNA activity was noted in the luminal and glandular structures. Active caspase-3 staining was increased in luminal epithelium and deep glandular cells during the luteal phase. However, in the follicular phase, stromal cells showed greater active caspase-3 expression. Only a few apoptotic endometrial cells were detected by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) and these cells were mostly present in luminal and glandular structures. A simultaneous increase in DNA, cell proliferation and protein synthesis was observed in the endometrium during the mid-luteal phase. This suggests that cell hyperplasia occurs at the time the histotroph is needed for eventual embryo nourishment.
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PMID:Caspase-3-mediated apoptosis and cell proliferation in the equine endometrium during the oestrous cycle. 1807 24

The aim of this study was to investigate the expression of p53, caspase-3, bcl-2, MIB-1, and PCNA to validate more objective methods to differentiate squamous cell carcinoma and keratoacanthoma, as well as to understand their pathogenesis with accuracy. A total of 52 cases of histopathologically diagnosed keratoacanthoma in the proliferative stage and 56 cases of well-differentiated squamous cell carcinoma were selected in this study. The expression was evaluated by means of immunohistochemistry. Bcl-2 immunoreactivity was weak or absent in the majority of cases, either in squamous cell carcinoma or in keratoacanthoma. PCNA-positive cells did not show differences between two lesions evaluated. On the other hand, MIB-1 was statistically significant (p<0.05) between squamous cell carcinomas and keratoacanthomas. Moreover, p53 and caspase-3 were overexpressed in squamous cell carcinomas. Together, these results suggest that the biological behavior of the well-differentiated squamous cell carcinomas of the skin may be associated with cellular proliferation and/or deregulation of cell death, indicated by increased expression of the MIB-1 and apoptotic proteins p53 and caspase-3, respectively.
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PMID:Expression of apoptotic and cell proliferation regulatory proteins in keratoacanthomas and squamous cell carcinomas of the skin. 1807 70


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