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)

Resveratrol, a polyphenolic phytoalexin found in grapes, may have potential for the prevention and treatment of human cancer. We report here that resveratrol inhibits the growth of human prostate carcinoma DU145 cells and provide a molecular explanation of the effect. Resveratrol treatment in DU145 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death. The antiproliferative effect of resveratrol was associated with the inhibition of D-type cyclins and cyclin-dependent kinase (Cdk) 4 expression, and the induction of tumor suppressor p53 and Cdk inhibitor p21. Moreover, the kinase activities of cyclin E and Cdk2 were inhibited by resveratrol without alteration of their protein levels. Resveratrol treatment also up-regulated the Bax protein and mRNA expression in a dose-dependent manner; however, Bcl-2 and Bcl-xL levels were not significantly affected. These effects were found to correlate with an activation of caspase-3 and caspase-9. Taken together, our study suggests that resveratrol has a strong potential for development as an agent for the prevention of human prostate cancer.
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PMID:Antiproliferative effect of resveratrol in human prostate carcinoma cells. 1497 34

The p53 tumor suppressor gene product plays an important role in the regulation of apoptosis. Transforming growth factor beta1 (TGF-beta1)-induced apoptosis in hepatic cells is associated with reduced expression of the retinoblastoma protein (pRb) and subsequent E2F-1-activated expression of apoptosis-related genes. In this study, we explored the potential role of p53 in TGF-beta1-induced apoptosis. HuH-7 human hepatoma cells were either synchronized in G1, S and G2/M phases, or treated with 1 nM TGF-beta1. The results indicated that greater than 90% of the TGF-beta1-treated cells were arrested in G1 phase of the cell cycle. This was associated with enhanced p53 dephosphorylation and p21(Cip1/Waf1) expression, which coincided with decreased Cdk2, Cdk4, and cyclin E expression, compared with synchronized G1 cells. In addition, p53 dephosphorylation coincided with caspase-3 activation, and translocation of p21(Cip1/Waf1) and p27(Kip1) into the cytoplasm, all of which were suppressed by caspase inhibition of TGF-beta1-induced apoptosis. Finally, phosphatase inhibition and pRb overexpression partially inhibited p53-mediated apoptosis. In conclusion, the results demonstrated that TGF-beta1-induced p53 dephosphorylation is associated with caspase-3 activation, and cytosolic translocation of p21(Cip1/Waf1) and p27(Kip1), resulting in decreased expression of Cdks and cyclins. Further, p53 appears to mediate TGF-beta1-induced apoptosis downstream of the pRb/E2F-1 pathway.
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PMID:p53 dephosphorylation and p21(Cip1/Waf1) translocation correlate with caspase-3 activation in TGF-beta1-induced apoptosis of HuH-7 cells. 1500 18

Nodal, a member of the transforming growth factor-beta superfamily, is known to play critical roles in early vertebrate development, but its functions in extraembryonic tissues are unclear. ALK7 is a type I receptor for Nodal. Recently, we demonstrated that Nodal mRNA and several ALK7 transcripts are expressed in human placenta throughout pregnancy (Roberts, H. J., Hu, S., Qiu, Q., Leung, P. C. K., Cannigia, I., Gruslin, A., Tsang, B., and Peng, C. (2003) Biol. Reprod. 68, 1719-1726). In this study, we determined the role of Nodal and ALK7 in trophoblast cell proliferation and apoptosis. Overexpression of Nodal in normal trophoblast cells (HTR8/SVneo) and several choriocarcinoma cell lines resulted in a significant decrease in the number of metabolically active cells. The effect of Nodal could be mimicked by constitutively active ALK7 (ALK7-ca), but was blocked by kinase-deficient ALK7. The growth inhibitory effect of Nodal was also blocked by dominant-negative Smad2/3. Overexpression of Nodal and ALK7-ca induced apoptosis in trophoblast cells as determined by Hoechst staining, flow cytometry, and caspase-3 Western blotting. In addition, Nodal and ALK7-ca decreased the number of proliferating cells as measured by bromodeoxyuridine assays. Furthermore, overexpression of Nodal or ALK7-ca increased p27 expression, but reduced the levels of Cdk2 and cyclin D(1). Taken together, this study demonstrates for the first time that Nodal, acting through ALK7 and Smad2/3, inhibits proliferation and induces apoptosis in human trophoblast cells. Our findings also suggest that the Nodal-ALK7 pathway inhibits cell proliferation by inducing G(1) cell cycle arrest and that this effect is mediated in part by the p27-cyclin E/Cdk2 pathway.
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PMID:Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. 1515 Feb 78

In this study, we have evaluated the chemopreventive role of aloe-emodin in human promyelocytic leukemia HL-60 cells in vitro by studying the regulation of proliferation, cell cycle and apoptosis. Aloe-emodin inhibited cell proliferation and induced G2/M arrest and apoptosis in HL-60 cells. Investigation of the levels of cyclins B1, E and A by immunoblot analysis showed that cyclin E level was unaffected, whereas cyclin B1 and A levels increased with aloe-emodin in HL-60 cells. Investigation of the levels of cyclin-dependent kinases, Cdk1 and 2, showed increased levels of Cdk1 but the levels of Cdk2 were not effected with aloe-emodin in HL-60 cells. The levels of p27 were increased after HL-60 cells were cotreated with various concentrations of aloe-emodin. The increase of the levels of p27 may be the major factor for aloe-emodin to cause G2/M arrest in these examined cells. Flow cytometric assays and DNA fragmentation gel electrophoresis also confirmed aloe-emodin induced apoptosis in HL-60 cells. The levels of caspase-3 were increased after HL-60 cells were cotreated with 10 microM aloe-emodin for 12, 24, 48, and 72 hours. Taken together, aloe-emodin therefore appears to exert its anticarcinogenesis properties by inhibiting proliferation and inducing cell cycle arrest and apoptosis underwent activation of caspase-3 in human leukemia HL-60 cells.
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PMID:Aloe-emodin induced in vitro G2/M arrest of cell cycle in human promyelocytic leukemia HL-60 cells. 1520 75

Diallyl disulfide (DADS), one of the major components of garlic (Allium sativum), is well known to have chemopreventative activity against human cancer such as colon, lung and skin. But the exact mechanism of the action is still unclear. In this study, we investigated how DADS--induced cell cycle arrest and apoptosis in T24 human bladder cancer cells in vitro. Apoptosis induction, cell viability, cell cycle arrest, caspases-3, -9 activity and gene expression were measured to determine their variation by flow cytometric assay, western blot, and determination of caspase-3 activity, PCR and cDNA microarray. There are significant differences in cell death (decreased viable cells then increased the amounts of apoptosis) of T24 cells that were detected between DADS (5-75 microM) treated and untreated groups. A significant increase was found in apoptosis induction when cells were treated with DADS (50 microM) compared to without DADS treated groups. DADS also promoted caspase-3 activity after exposure for 1, 3, 6, 12, and 24 h, which led to induce apoptosis. DADS also increased the product of intracellular hydrogen peroxide. Furthermore, the DADS-induced apoptosis on T24 cells was blocked by the broad-spectrum caspase inhibitor, z-VAD-fmk and antioxidant (catalase). DADS also increased cyclin E and decreased CDK2 gene expression which may lead to the G2/M arrest of T24 cells.
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PMID:Diallyl disulfide (DADS) induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells. 1530 1

The TRIP-Br family of transcriptional regulators (TRIP-Br1 and TRIP-Br2) has been proposed to function at E2F-responsive promoters to integrate regulatory signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. To characterize the TRIP-Br "integrator" function(s), we have employed decoy peptides (*Br1 and *Br2) to antagonize the interaction between TRIP-Br1 or TRIP-Br2 and the PHD zinc finger and/or bromodomain of other transcription factors. Antagonism of the TRIP-Br integrator function elicits anti-proliferative effects through the transcriptional downregulation of a subset of E2F-responsive genes in vivo, and induces aberrant cyclin E accumulation, leading to Geminin deregulation and caspase-3-independent cellular sub-diploidization. The observed cyclin E deregulation is attributed to the downregulation of Fbxw7, which encodes the Fbw7 receptor subunit of the SCF(FBW7) ubiquitin ligase (E3) responsible for targeting cyclin E for proteolysis. Fbxw7 is identified herein as an E2F-responsive and TRIP-Br coregulated gene. Our results demonstrate a physiologic role for TRIP-Br in coupling E2F to novel functions in the regulation of cyclin E expression during cell cycle progression to ensure the proper execution of DNA replication and the maintenance of genomic stability.
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PMID:TRIP-Br links E2F to novel functions in the regulation of cyclin E expression during cell cycle progression and in the maintenance of genomic stability. 1546 69

S-phase kinase associated protein (Skp) 2 is an F-box protein required for substrate recognition of the SCF(Skp2) ubiquitin ligase complex. Skp2 is often overexpressed in transformed cells and in various types of tumors. Downregulation or inhibition of Skp2 inhibits growth of breast cancer cells and small-cell lung carcinoma cells. We downregulated Skp2 in T98G glioblastoma cells using small interfering RNA (siRNA). Downregulation induced p27 and caused growth arrest and apoptosis. Downregulation of both Skp2 and p27 increased apoptosis synergistically. Cyclin E levels and cyclin E-CDK2 kinase activity increased dramatically when both Skp2 and p27 were downregulated. Coincidently, Bcl-2 but not Bcl-xL expression decreased, and caspase-3 was activated. Inhibition of cyclin E-CDK2 kinase activity by forced expression of p21 reversed these effects. Moreover, stable expression of Bcl-2 also abrogated apoptosis induced by downregulation of Skp2 and p27. We suggest that Skp2 in tumor cells suppresses apoptosis through Bcl-2 expression, potentially through regulation of cyclin E-CDK2 activity.
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PMID:Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. 1560 73

Familial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH. Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers.
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PMID:Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. 1577 May 21

The vascular endothelial growth factor (VEGF) is known mainly as the potent angiogenic and vascular permeability-enhancing factor. Both processes are very effective in hypoxia. The latest studies show that VEGF has neurotrophic and neuroprotective as well as angiogenic properties. It exerts neuroprotective actions directly through the inhibition of programmed cell death (PCD), or apoptosis and the stimulation of neurogenesis. VEGF is also a mediator of multiple processes including angiogenesis, enhancing blood brain barrier permeability for glucose, antioxidants activation, which indirectly result in neuroprotection. VEGF prevents neurons from death under critical conditions such as hypoxia, glucose deprivation through binding to the specific receptors, which are also expressed on the surface of neuronal cells. The increased expression of VEGFR-2/flk-1/KDR receptors on neurons subjected to hypoxia, glucose deprivation provides evidence that these receptors are mainly involved in neuroprotective effects of VEGF. Furthermore, binding to these receptors triggers the phosphatidyloinositol 3-kinase (PI3K) /Akt signal transduction system and, in consequence, leads to the inhibition of PCD by activating antiapoptotic proteins through the transcription factor NFkappaB and inhibiting proapoptotic signaling by Bad, caspase-9, caspase-3, and other effectors. Promotion of neuronal cells proliferation by VEGF is also associated with the increased expression of VEGFR-2 receptors and up-regulation of E2F family transcription factors, cyclin D1, cyclin E, and cdc25. It is known that the amount and types of VEGF isoforms influence its action. At least six isoforms of VEGF proteins are formed as a result of alternative mRNA splicing and it is unknown which of them and in what proportion occur in the nervous system in physiology and pathophysiology. It seems to be very essential to find out the mechanisms responsible for specific patterns of VEGF isoforms and their receptors expression in different pathologies of the nervous system. Maybe such knowledge will provide new perspectives in VEGF therapy.
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PMID:The neuroprotective function of vascular endothelial growth factor (VEGF). 1582 88

1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I6), a gingerdione derivative, was synthesized in our laboratory, has been demonstrated to be an effective anti-tumor agent in human leukemia cells. Gingerdione is one of the components from ginger. In the present study, we found that I6 could inhibit cell proliferation in the time- and dose-dependent manner in human promyelocytic leukemia HL-60 cells. To investigate the anti-proliferation mechanism of I6, cell cycle analysis was performed. Results showed that I6 induced significant G1 arrest and apoptosis in HL-60 cells. It was proved by the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of regulatory on G1 arrest that the levels of p15 and p27 increased after treatment and mRNA levels of cyclin D2, cyclin E, and cdc25A were decreased. The I6-induced apoptosis was further confirmed by DNA fragmentation assay. The DNA gel electrophoresis showed that I6 induced DNA fragmentation, a biochemical hallmark of apoptosis, in HL-60 cells. I6-induced apoptosis was accompanied by an apparent up-regulation of caspase-3, and down-regulation of Bcl-2. Taken together, these results suggest that markedly down-regulation of G1 associated cyclin D2, cyclin E and cdc25A and up-regulation of CDKI, p15 and p27, and may contribute to I6-mediated cell cycle arrest. Furthermore, the Bcl-2 expression decrease and caspase-3 activation may be the plausible mechanism by which I6 induced apoptosis. These results suggest that I6 is a potent anti-HL-60 drug and possess a significant action on cell cycle before commitment for apoptosis occurrence.
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PMID:1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I6) induces G1 arrest and apoptosis in human promyelocytic leukemia HL-60 cells. 1592 54


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