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

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cetuximab (Erbitux) is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody whose activity is related to the inhibition of EGFR downstream signaling pathways. P53 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been reported to control the functionality of PI3K/AKT signaling. In this study we evaluated whether reintroducing P53 using non-viral gene transfer enhances PTEN-mediated inhibition of PI3K/AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations. Signaling phosphoproteins expression was analyzed using Bio-Plex phosphoprotein array and western blot. Apoptosis induction was evaluated from BAX expression, caspase-3 activation and DNA fragmentation analyses. The results presented show that p53 and pten gene transfer additionally mediated cell growth inhibition and apoptosis induction by restoral of signaling functionality, which enabled the control of PI3K/AKT and MAPKinase signaling pathways by cetuximab in PC3 cells. These results highlight the interest of the analysis of signaling phosphoproteins expression as molecular predictive markers for response to cetuximab and show that p53 and pten mutations could be key determinants of cell response to cetuximab through the functional impact of these mutations on cell signaling.
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PMID:P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab. 1916 35

Truncated tau is widely detected in Alzheimer's disease brain, and caspase-3 has been considered as a major executioner for tau truncation at aspartate421 (D421), according to its capability of cleaving recombinant tau in vitro. Here we investigated the relationship between D421 truncated tau and caspase-3 in two transgenic mouse models for tauopathies. In adult transgenic mice, activated caspase-3 could not be detected in neurons containing truncated tau, with the exception of a few glia-like cells or neurons in postnatal mice. Caspase-3 expression exhibited a dramatic decrease at the early development stage, and kept at constantly low levels during adult stages in both wild type and transgenic mice. On the other hand, co-incubating brain homogenates from adult tau transgenic mice and ethanol-treated postnatal mice promoted tau truncation at D421, which was mildly reduced by caspase inhibitor, but completely suppressed by phosphatase inhibitor, indicating that hyperphosphorylated tau becomes a poor substrate for truncation at D421. Taken together, our study shows that insufficient caspase-3 expression and hyperphosphorylated status of tau in the adult transgenic mouse brain restrict caspase-3 as an efficient enzyme for tau truncation in vivo. Clearly, there is a caspase-3 independent mechanism responsible for tau truncation at D421 in these models.
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PMID:Role of caspase-3 in tau truncation at D421 is restricted in transgenic mouse models for tauopathies. 1920 Mar 47

The src homology 2 (SH2)-domain containing inositol-5-phosphatase (SHIP) is another recently identified lipid phosphatase after phosphatase and tensin homology deleted on chromosome ten gene (PTEN). It plays an important role in negatively regulating the proliferation of hematopoietic cells. The relationship between SHIP and the inhibition of tumor proliferation is rarely reported. The purpose of this study is to evaluate the apoptosis induced by SHIP gene in K562 cell line and to explore the involved signaling pathway. The K562 cells were transfected with human SHIP gene by using the lentiviral vector containing SHIP, and the transfection was verified by fluorescent quantitative PCR (FQ-PCR) and Western blot. Then the effects of SHIP protein expression on cell growth and apoptosis were measured. The levels of p-Akt, bcl-2 family, caspase and the activity of NFkappaB were assayed by Western blot and ELISA, respectively. The results are as follows: (1) Human leukemia cell line K562 was SHIP-negative; (2) Transfection with SHIP gene led to the re-expression of SHIP mRNA and protein in K562, as shown by FQ-PCR and Western blot; (3) The expression of SHIP protein inhibited cell growth and significantly increased apoptosis in K562 cells; (4) Compared to that in control group, the expression level of p-Akt-308 and p-Akt-473 in SHIP-expressing cell group decreased significantly (P<0.01); SHIP activated caspase-9, caspase-3, up-regulated protein levels of bad, p27, down-regulated expression of bcl-xL, while it had no effect on the expression of bcl-2 and bax. Furthermore, the inhibition of NF-kappaB was achieved along with the inactivation of Akt. These data suggest that SHIP gene has potential abilities to inhibit K562 leukemic cell proliferation and induce its apoptosis via inactivating PI3K/Akt pathway. The loss of SHIP might be the explanation of aberrant high-level p-Akt in human leukemia. It may be at least one of the mechanisms by which the loss of SHIP expression contributes to leukemia progression.
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PMID:[The mechanism for SHIP gene to induce the apoptosis of human leukemia cell line K562.]. 1937 26

Cd is an industrial and environmental pollutant that affects many organs in humans and other mammals. However, the molecular mechanisms of Cd-induced nephrotoxicity are unclear. In this study, we show that endoplasmic reticula (ER) played a pivotal role in Cd-induced apoptosis in mesangial cells. Using Fluo-3 AM, the intracellular concentration of calcium ([Ca(2+)](i)) was detected as being elevated as time elapsed after Cd treatment. Co-treatment with BAPTA-AM, a calcium chelator, was able to significantly suppress Cd-induced apoptosis. Calcineurin is a cytosolic phosphatase, which was able to dephosphorylate the inositol-1,4,5-triphosphate receptor (IP(3)R) calcium channel to prevent the release of calcium from ER. Cyclosporine A, a calcineurin inhibitor, increased both [Ca(2+)](i) and the percentage of Cd-induced apoptosis. However, EGTA and the IP(3)R inhibitor, 2-APB, were able to partially modulate Cd cytotoxicity. These results led us to suggest that the extracellular and ER-released calcium plays a crucial role in Cd-induced apoptosis in mesangial cells. Following this line, we further detected the ER stress after Cd treatment since ER is one of the major calcium storage organelles. After Cd exposure, GADD153, a hallmark of ER stress, was upregulated (at 4h of exposure), followed by activation of ER-specific caspase-12 and its downstream molecule caspase-3 (at 16h of exposure). The pan caspase inhibitor, Z-VAD, and BAPTA-AM were able to reverse the Cd-induced cell death and ER stress, respectively. Furthermore, the mitochondrial membrane potential (DeltaPsi(m)) was depolarized significantly and cytochrome c was released after 24h of exposure to Cd and followed by mild activation of caspase-9 at the 36-h time point, indicating that mitochondria stress is a late event. Therefore, we concluded that ER is the major killer organelle in Cd-induced mesangial cell apoptosis and that calcium oscillation plays a pivotal role.
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PMID:The role of endoplasmic reticulum in cadmium-induced mesangial cell apoptosis. 1944 55

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is a phosphatase that antagonizes the phosphoinositol-3-kinase/AKT signaling pathway and suppresses cell survival as well as cell proliferation. To investigate the molecular role of PTEN expression and mutation in colorectal carcinomas, we performed immunohistochemistry to detect PTEN expression on tissue microarray containing colorectal carcinomas and corresponding adjacent non-cancerous mucosa. PTEN mutation was studied from exon 1 to 9 by PCR, followed by direct sequencing. PTEN expression was then compared with clinicopathological parameters and prognosis of the tumor, including caspase-3 expression. In the present study, PTEN expression was stronger in the adjacent non-cancerous mucosa than carcinoma (P<0.001). Low PTEN expression was positively correlated with tumor size, depth of invasion, lymphatic invasion, lymph node metastasis, higher Dukes staging and reduced caspase-3 expression (P<0.05), but not with venous invasion or differentiation (P>0.05). Univariate analysis suggested that the patients without PTEN expression had shorter survival than the patients with its expression (P=0.003). Multivariate analysis indicated that lymphatic invasion, venous invasion, and PTEN expression were independent prognostic factors for overall colorectal carcinomas (P<0.05). The analysis of mutations revealed only one synonymous mutation in exon 8 (codon 312 Asp: GACright curved arrow GAT). These results suggested that down-regulated PTEN expression was involved in the pathogenesis, invasion and metastasis of colorectal carcinomas possibly by regulating the balance between apoptosis and proliferation. PTEN expression may be a good marker for the prognosis of colorectal carcinoma.
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PMID:PTEN expression and mutation in colorectal carcinomas. 1972 53

In previous works, we found that PTH promotes the apoptosis of human Caco-2 intestinal cells, through the mitochondrial pathway. This study was conducted to investigate the modulation of different players implicated in the AKT survival pathway in PTH-induced intestinal cell apoptosis. We demonstrate, for the first time, that PTH modulates AKT phosphorylation in response to apoptosis via the serine/threonine phosphatase PP2A. PTH treatment induces an association of AKT with the catalytic subunit of PP2A and increases its phosphatase activity. PTH also promotes the translocation of PP2Ac from the cytosol to the mitochondria. Furthermore, our results suggest that PP2A plays a role in hormone-dependent Caco-2 cells viability and in the cleavage of caspase-3 and its substrate PARP. The cAMP pathway also contributes to PTH-mediated AKT dephosphorylation while PKC and p38 MAPK do not participate in this event. Finally, we show that PTH induces the dissociation between 14-3-3 and AKT, but the significance of this response remains unknown. In correlation with PTH-induced Bad dephosphorylation, the hormone also decreases the basal association of 14-3-3 and Bad. Overall, our data suggest that in Caco-2 cells, PP2A and the cAMP pathway act in concert to inactivate the AKT survival pathway in PTH-induced intestinal cell apoptosis.
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PMID:PTH inactivates the AKT survival pathway in the colonic cell line Caco-2. 2000 8

When cells attach to the extracellular matrix (ECM) a proliferation permissive signal is engaged. The mechanism involves activation of the integrin/PI3K/Akt signal pathway. FoxO3a is a transcriptional activator and inhibits cell proliferation via up-regulating the expression of the cell cycle inhibitor p27. Furthermore, it is known that activated Akt can suppress FoxO3a function. However, it is not known whether integrin interaction with the ECM regulates FoxO3a function. We examined whether the beta1-integrin-mediated signaling pathway promotes fibroblast proliferation via FoxO3a suppression. We found that when fibroblasts are attached to collagen, PTEN protein expression and activity are inhibited due to promotion of PTEN degradation. This decrease in PTEN function permits FoxO3a suppression via the PI3K/Akt pathway. In contrast, the inhibition of PI3K/Akt or reconstitution of PTEN restores FoxO3a expression on collagen. Furthermore, we found that the serine/threonine phosphatase PP2A also regulates FoxO3a. PP2A expression/activity is low when fibroblasts are attached to collagen, and PP2A overexpression augments FoxO3a levels. Thus the mechanism involves a coordinated decrease in PTEN and PP2A phosphatase activity and increase in PI3K/Akt activity. We show that beta1-integrin-ECM interaction decreases FoxO3a protein levels via caspase-3-mediated cleavage. Our novel finding indicates that during fibroblast interaction with ECM, activation of beta1-integrin/PI3K/Akt by inhibiting PTEN in combination with low PP2A phosphatase activity synergistically inhibits FoxO3a, promoting fibroblast proliferation.
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PMID:beta1-Integrin-collagen interaction suppresses FoxO3a by the coordination of Akt and PP2A. 2022 31

Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP kinase kinase kinase, is activated by several death stimuli and is tightly regulated by several mechanisms such as interactions with regulatory proteins and post-translational modifications. Here, we report that dual-specificity phosphatase 13A (DUSP13A) functions as a novel regulator of ASK1. DUSP13A interacts with the N-terminal domain of ASK1 and induces ASK1-mediated apoptosis through the activation of caspase-3. DUSP13A enhances ASK1 kinase activity and thus its downstream factors. Small interfering RNA (siRNA) analyses show that knock-down of DUSP13A in human neuroblastoma SK-N-SH cells reduces ASK1 kinase activity. The phosphatase activity of DUSP13A is not required for the regulation of ASK1. This regulatory action of DSUP13 on ASK1 activity involves competition with Akt1, a negative regulator of ASK1, for binding to ASK1. Taken together, this study provides novel insights into the role of DUSP13A in the precise regulation of ASK1.
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PMID:Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13A. 2035 50

Angiotensin II (Ang II) is a key proapoptotic factor in fibrotic tissue diseases. However, the mechanism of Ang-II-induced cell death in endothelial cells has not been previously elucidated. Using the neutral comet assay and specific receptor antagonists and agonists, we found that Ang-II-mediated apoptosis in primary pulmonary endothelial cells required the AT2 receptor. Ang II caused cytochrome c release from the mitochondria concurrent with caspase-3 activation and DNA fragmentation, and apoptosis was suppressed by an inhibitor of Bax-protein channel formation, implicating mitochondrial-mediated apoptosis. There was no evidence that the extrinsic apoptotic pathway was involved, because caspase-9, but not caspase-8, was activated by Ang-II treatment. Apoptosis required phosphoprotein phosphatase activation, and inhibition of the SHP-2 phosphatase (encoded by Ptpn11) blocked cell death. Reduced levels of anti-apoptotic Bcl-2-family members can initiate intrinsic apoptosis, and we found that Ang-II treatment lowered cytosolic Bcl-x(L) protein levels. Because the protein nucleolin has been demonstrated to bind Bcl-x(L) mRNA and prevent its degradation, we investigated the role of nucleolin in Ang-II-induced loss of Bcl-x(L). RNA-immunoprecipitation experiments revealed that Ang II reduced the binding of nucleolin to Bcl-x(L) mRNA in an AU-rich region implicated in instability of Bcl-x(L) mRNA. Inhibition of SHP-2 prevented Ang-II-induced degradation of Bcl-x(L) mRNA. Taken together, our findings suggest that nucleolin is a primary target of Ang-II signaling, and that Ang-II-activated SHP-2 inhibits nucleolin binding to Bcl-x(L) mRNA, thus affecting the equilibrium between pro- and anti-apoptotic members of the Bcl-2 family.
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PMID:Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells. 2040 88

The function of protein phosphatases with EF-hand domains (PPEF) in mammals is not known. Large-scale expression profiling experiments suggest that PPEF expression may correlate with stress protective responses, cell survival, growth, proliferation, or neoplastic transformation. Apoptosis signal regulating kinase-1 (ASK1) is a MAP kinase kinase kinase implicated in cancer, cardiovascular and neurodegenerative diseases. ASK1 is activated by oxidative stress and induces pro-apoptotic or inflammatory signalling, largely via sustained activation of MAP kinases p38 and/or JNK. We identify human PPEF2 as a novel interacting partner and a negative regulator of ASK1. In COS-7 or HEK 293A cells treated with H(2)O(2), expression of PPEF2 abrogated sustained activation of p38 and one of the JNK p46 isoforms, and prevented ASK1-dependent caspase-3 cleavage and activation. PPEF2 efficiently suppressed H(2)O(2)-induced activation of ASK1. Overexpessed as well as endogenous ASK1 co-immunoprecipitated with PPEF2. PPEF2 was considerably more potent both as a suppressor of ASK1 activation and as its interacting partner as compared to protein phosphatase 5 (PP5), a well-known negative regulator of ASK1. PPEF2 was found to form complexes with endogenous Hsp70 and to a lesser extent Hsp90, which are also known interacting partners of PP5. These data identify, for the first time, a possible downstream signalling partner of a mammalian PPEF phosphatase, and suggest that, despite structural divergence, PPEF and PP5 phosphatases may share common interacting partners and functions.
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PMID:Protein phosphatase with EF-hand domains 2 (PPEF2) is a potent negative regulator of apoptosis signal regulating kinase-1 (ASK1). 2067 65


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