Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipocyte number, a determinant of adipose tissue mass, reflects the balance between the rates of proliferation/differentiation vs. apoptosis of preadipocytes. The percentage of 3T3-L1 preadipocytes undergoing cell death following serum deprivation was reduced by 10 nM insulin-like growth factor (IGF)-1 (from 50.0 +/- 0.7% for control starved cells to 27.5 +/- 3.1%). TUNEL staining confirmed the apoptotic nature of the cell death. The protective effect of IGF-1 was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin, and LY294002, but was unaffected by rapamycin, PD98059, or SB203580, which inhibit mammalian target of rapamycin (mTOR), ERK kinase (MEK1), and p38 MAPK respectively. Exogenous PI(3,4,5)P3 (10 microM), the principal product of IGF-1-stimulated PI3K in 3T3-L1 preadipocytes, had a modest survival effect on its own, reducing cell death from 47.9 +/- 3.4% to 35.6 +/- 3.5%. When added to the combination of IGF-1 and LY294002, PI(3,4,5)P3 reversed most of the inhibitory effect of LY294002 on IGF-1-dependent cell survival, protein kinase B/Akt phosphorylation, and caspase-3 activity. Taken together, these results implicate PI(3,4,5)P3 as a necessary signal for the anti-apoptotic action of IGF-1 on 3T3-L1 preadipocytes.
...
PMID:Phosphatidylinositol-3,4,5-trisphosphate is required for insulin-like growth factor 1-mediated survival of 3T3-L1 preadipocytes. 1114 83

In order to investigate a possible effect of insulin-like growth factor-1 (IGF-1) on ischemic brain injury, IGF-1 was applied topically on the brain surface of reperfused rat brain after 60 min of transient middle cerebral artery occlusion. In contrast to the cases treated with vehicle, the infarct volume was greatly reduced at 24 h of reperfusion by the treatment with IGF-1. Immunohistochemical analysis in the middle cerebral artery territory showed that Caspase-3 staining was markedly reduced in the cases with IGF-1 treatment, but 72-kDa heat shock protein staining remained almost unchanged. The present results suggest that treatment with IGF-1 exerts a significant effect on ameliorating brain injury after transient focal brain ischemia. Moreover, this effect is greatly associated with the reduction of Caspase-3 staining, but is only minimally associated with a decreasd stress response at the cellular level.
...
PMID:Reduction of ischemic damage by application of insulin-like growth factor-1 in rat brain after transient ischemia. 1124 74

A characteristic hallmark of Alzheimer's disease brain is the presence of hyperphosphorylated tau; however, the mechanisms responsible for the aberrant tau phosphorylation are unknown. Recently, it has been shown that apoptotic-like processes may be involved in some of the neuronal loss in Alzheimer's disease. In consideration of these findings, the relationship between tau phosphorylation and apoptosis was examined in human neuroblastoma SH-SY5Y cells that were subjected to hyperosmotic stress. In this model caspase 3 activity, which served as an indicator of apoptosis, was increased by 30 min of osmotic stress and remained elevated through 4 hr. Hyperosmotic stress also resulted in a robust increase in tau phosphorylation at both Ser/Pro and non-Ser/Pro sites. Phosphorylation of Ser262/356 (12E8) and Ser396/404 (PHF-1) increased by 5 min and remained elevated for at least 1 hr. In contrast, phosphorylation within the Tau-1 epitope did not increase (as evidenced by decreased immunoreactivity) until 30 min after treatment but remained elevated for a much greater period of time. Treatment with insulin-like growth factor-1 delayed but did not prevent apoptotic cell death induced by osmotic stress and attenuated the increase in phosphorylation at the Tau-1 epitope. Li(+), an inhibitor of glycogen synthase kinase 3 beta, had no effect on osmotic stress-induced caspase activation, but reduced phosphorylation at the Tau-1 epitope. Complete inhibition of osmotic stress-induced caspase activation with DEVD-CHO had no effect on the increases in tau phosphorylation. The results of these studies demonstrate that tau phosphorylation is increased at the specific epitopes during apoptosis. However, the changes in tau phosphorylation likely do not significantly impact the apoptotic process but rather occur concurrently as a result of inappropriate activation of specific protein kinases. Nonetheless, there is increasing evidence of a dysregulation of protein kinases that occurs in Alzheimer's disease brain that may be part of the events of apoptosis, which could contribute to aberrant increases in tau phosphorylation.
...
PMID:Hyperosmotic stress-induced apoptosis and tau phosphorylation in human neuroblastoma cells. 1155 Feb 25

The compound 1-methyl-4-phenylpyridinium (MPP) is a selective inhibitor of mitochondrial complex I, and is widely used in model systems to elicit neurochemical alterations that may be associated with Parkinson's disease. In the present study treatment of human neuroblastoma SH-SY5Y cells with MPP resulted in a time- and concentration-dependent activation of the apoptosis-associated cysteine protease caspase-3, and caused morphological changes characteristic of apoptosis. To test if the activation state of the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway affects MPP-induced caspase-3 activation, PI3K was inhibited with LY294002, or activated with insulin-like growth factor-1. MPP-induced caspase-3 activation was increased by inhibition of PI3K, and decreased by stimulation of PI3K, indicative of anti-apoptotic signaling by the PI3K/Akt pathway. To test if glycogen synthase kinase-3beta (GSK3beta), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3beta and lithium, a selective inhibitor of GSK3beta, were used to directly alter GSK3beta activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3beta. Conversely, the GSK3beta inhibitor lithium attenuated MPP-induced caspase-3 activation. To test if these regulatory interactions applied to other mitochondrial complex I inhibitors, cells were treated with rotenone. Rotenone-induced activation of caspase-3 was enhanced by inhibition of PI3K or increased GSK3beta activity, and was attenuated by inhibiting GSK3beta with lithium. Overall, these results indicate that inhibition of GSK3beta provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.
...
PMID:Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. 1168 67

Phospholipase C-gamma1, a tyrosine kinase substrate, hydrolyses phosphatidylinositol 4,5-bisphosphate to produce inositol 1,4,5-trisphosphate and diacylglycerol, which act as second messenger moleculesto mobilize intracellular calcium and activate protein kinase C, respectively. We have investigated the role of phospholipase C-gamma1 in anoikis, or cell death, induced by the loss of extracellular matrix adhesion. Spontaneously immortalized mouse embryonic fibroblasts nullizygous at the Plcg1 locus (Plcg1(-/-)), referred to as Null cells, were derived from targeted gene disruption experiments. Subsequently, phospholipase C-gamma1 was re-expressed in these cells to derive Null+ cells. The Null and Null+ cells were then placed in suspension to induce cell death, which was measured directly as well as by the induction of caspase 3, as an index of programmed cell death or apoptosis. The results demonstrate that insulin-like growth factor can rescue Null+ cells but not Null cells from suspension-induced cell death. This demonstrates that phospholipase C-gamma1 is required for insulin-like growth factor dependent cell survival under these conditions. Lastly, the data demonstrate that insulinlike growth factor stimulated tyrosine phosphorylation of phospholipase C-gamma1 in both adherent and suspension cells.
...
PMID:PLC-gamma1 is required for IGF-I protection from cell death induced by loss of extracellular matrix adhesion. 1197 63

Insulin-like growth factors (IGFs) have mitogenic and antiapoptotic properties and have been implicated in the development of lung cancer. The effects of IGFs are modulated by insulin-like growth factor binding proteins (IGFBPs). This study explored the effects of IGFBP-3 on non-small cell lung cancer (NSCLC) cells after infection with an adenovirus constitutively expressing IGFBP-3 under the control of the cytomegalovirus promoter (Ad5CMV-BP3). We found that IGFs, especially IGF-I, stimulated the growth of NSCLC cells, and Ad5CMV-BP3 suppressed this IGF-I-induced NSCLC cell growth. We also found that the clonogenicity of H1299 cells in soft agar was markedly reduced by Ad5CMV-BP3. Furthermore, direct injection of Ad5CMV-BP3 into H1299 NSCLC xenografts s.c. established in athymic nude mice induced massive destruction of the tumors. Ad5CMV-BP3 did not induce detectable cytotoxicity on normal human bronchial epithelial cells, suggesting therapeutic efficacy of this virus. Ad5CMV-BP3 infection was accompanied by apoptotic cell death in vitro as detected by flow cytometry, DNA fragmentation analysis, and Western blot analysis on the expression of Bcl-2 and on the cleavage of poly(ADP-ribose) polymerase, a substrate of caspase 3. Immunofluorescence confocal microscopy was also used to show the apoptotic effect of Ad5CMV-BP3 in H1299 tumors established in nude mice. These findings indicated that IGFBP-3 was a potent inducer of apoptosis in NSCLC cells in vitro and in vivo. To delineate the underlying mechanism, we examined the effect of IGFBP-3 on Akt/protein kinase B and glycogen synthase kinase-3beta, downstream mediators of the phosphatidylinositol 3-kinase pathway, and on mitogen-activated protein kinase (MAPK), all three of which are activated by IGF-mediated signaling pathways and have important roles in cell survival. IGFBP-3 overexpression inhibited the phosphorylation of Akt and glycogen synthase kinase-3beta and the activity of MAPK. Furthermore, IGF-I rescued the NSCLC cells from serum depletion-induced apoptosis, and this rescue was blocked in Ad5CMV-BP-3-infected H1299 NSCLC cells. Transient transfection with activated Akt or constitutively active MAPK kinase-1, an upstream activator of MAPK, partially blocked IGFBP-3-induced apoptosis of NSCLC cells. These findings suggested that the growth-regulatory effect of IGFBP-3 on NSCLC cells was attributable in part to the inhibition of the IGF-induced survival pathway. These data demonstrate the importance of IGFBP-3 in the regulation of NSCLC cell proliferation, clonogenicity, and tumor growth, suggesting that IGFBP-3 is a target for the treatment of lung cancer and that Ad5CMV-BP3 is a potential therapeutic agent.
...
PMID:Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer. 1206

Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca(2+)-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3beta (GSK3beta). Activation of GSK3beta was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant-negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3beta by inducing dephosphorylation of phospho-Ser-9 of GSK3beta, a phosphorylation that normally maintains GSK3beta inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3beta with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3beta through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
...
PMID:Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. 1222 24

The aim of the present study was to investigate the action of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) on steroidogenesis and apoptosis in human corpus luteum during the midluteal phase. Slices from corpora lutea were incubated for 4 h with IGF-I or IGFBP-3. Progesterone, oestradiol, androstenedione and testosterone concentrations were determined by radioimmunoassay; caspase 3 expression was assessed by immunohistochemistry; bcl-2, bax and P(450arom) expression were assessed by RT-PCR; and apoptosis was detected by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. The results showed that addition of IGF-I stimulated progesterone production (150%, P < 0.01), oestradiol production (65%, P < 0.05) and bcl-2 gene expression (approximately 200%, P < 0.05), but decreased apoptosis (P < 0.05). In contrast, IGFBP-3 reduced steroid production and increased bax gene expression and the percentage of apoptotic cells (P < 0.05). Neither IGF-I nor IGFBP-3 had an effect on P(450arom) expression or on the concentrations of its substrates. However, maximum expression of caspase 3 was detected in corpus luteum during the midluteal phase. In conclusion, these results indicate that IGF-I and IGFBP-3 act as regulatory peptides of the function of the human corpus luteum during the midluteal phase. This action may be direct or mediated by steroid production or by bcl-2-bax expression.
...
PMID:Regulation of steroid synthesis and apoptosis by insulin-like growth factor I and insulin-like growth factor binding protein 3 in human corpus luteum during the midluteal phase. 1236 68

The basic leucine zipper containing activating transcription factors (ATFs) modulates the expression of growth-regulating genes. In this study, we sought to determine specifically the consequences of ATF4 expression on mammary gland development in transgenic mice. Overexpression of ATF4 severely impaired normal development of the mammary gland, which was associated with reduced proliferation and differentiation of mammary alveolar epithelium and up-regulation of p21(WAF1) and p27(Kip1). In addition, there was also impaired lactation accompanied by decreased expression of alpha-lactoalbumin, whey acidic protein, and beta-casein, possibly because of the down-regulation of STAT5a tyrosine phosphorylation. Mammary gland involution in ATF4-transgenic mice was accelerated, compared with wild type littermates by whole mount analysis. In addition, day 18 of lactation in transgenic mice was phenotypically equivalent to day 3 of involution in wild type mice, as determined by the TUNEL assay and expression of Bax. The concentration of the proapoptotic molecule caspase-3 was increased during lactation in ATF4-transgenic animal. Mammary glands from ATF4-transgenic mice also showed significant nuclear translocation of activated STAT3 and up-regulation of one of its target genes, insulin-like growth factor-binding protein-5, which is thought to facilitate apoptosis by sequestering insulin-like growth factor. Together, these findings suggest that ATF4 may play a role during mammary gland development and that down-regulation of ATF4 may be important for the onset of involution in the mammary gland.
...
PMID:Activating transcription factor 4 overexpression inhibits proliferation and differentiation of mammary epithelium resulting in impaired lactation and accelerated involution. 1261 81

Selective inhibition of neuronal and inducible nitric oxide synthase (NOS) with 2-iminobiotin previously showed a reduction in brain cell injury. In the present study, we investigated the effects of 2-iminobiotin treatment on insulin-like growth factor-1 (IGF-1) expression, caspase activity and cytokine expression in a newborn piglet model of perinatal hypoxia-ischaemia. Newborn piglets were subjected to 1 h of hypoxia-ischaemia and were treated intravenously with vehicle or 2-iminobiotin. Vehicle-treated piglets showed reduced IGF-1 mRNA expression and increased caspase-3 activity and DNA fragmentation. 2-Iminobiotin treatment, administered immediately upon reperfusion, prevented these observations. No differences in caspase-8 and -9 activity and cytokine [interleukin (IL)-1alpha/beta, IL-6, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta] mRNA expression were demonstrated between vehicle- and 2-iminobiotin-treated piglets at 24 h following hypoxia-ischaemia. IGF-1 mRNA correlated inversely with caspase-3 and transferase-mediated dUTP-biotin in situ nick end labelling score in the cortex, but positively with caspase-8. Cytokine mRNA did not correlate with IGF-1 mRNA, caspase-3 activity or DNA fragmentation. The present results indicate that the previously demonstrated neuroprotective effect of 2-iminobiotin treatment after perinatal hypoxia-ischaemia coincided with a preservation of the endogenous IGF-1 production and reduced caspase-3 activity, but not with a significant decrease in cytokine production.
...
PMID:Effects of selective nitric oxide synthase inhibition on IGF-1, caspases and cytokines in a newborn piglet model of perinatal hypoxia-ischaemia. 1264 Jan 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---