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)

Apoptosis is instrumental in the processes generating the diversity of the B-cell repertoire. Autoreactive B-cells are eliminated by anti-IgM crosslinking after encountering self-antigens, but precise mechanisms leading to B-cell apoptosis are still not well understood. We report here the cleavage of the transcription factor SP1 in the human Burkitt lymphoma cell line BL60 during anti-IgM-induced apoptosis. Western blot analysis revealed two cleavage products of approximately 68 kDa and 45 kDa after induction of apoptosis. Cleavage could be completely inhibited by zDEVD-fmk, an inhibitor specific for caspase 3-like proteases. In-vitro cleavage of recombinant SP1 by recombinant caspase 3 (CPP32) or caspase 7 (Mch 3) results in similar cleavage products as those observed in vivo. Recombinant caspase 6 (Mch 2) primarily generates a 68-kDa cleavage product, as observed after calcium ionophore (CaI) induced B-cell apoptosis. In contrast, caspase 1 (ICE) did not cleave SP1 in vitro. The time course of SP1 cleavage during anti-IgM-induced apoptosis is paralleled by an increase of caspase activity measured by DEVD-p-nitroanilide (DEVD-pNA) cleavage. DNA band-shift assays revealed a decrease in the intensity of the full length SP1/DNA complex and an increase in the intensity of a smaller complex due to the binding of one SP1 cleavage product. By Edman sequencing we could identify a caspase 3 cleavage site after Asp584 (D584AQPQAGR), generating a 22-kDa C-terminal SP1 protein fragment which still contains the DNA binding site. Our results show the cleavage of the human transcription factor SP1 in vivo and in vitro, underlining the central role of caspase 3-like proteases during the process of anti-IgM-induced apoptosis.
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PMID:Cleavage of transcription factor SP1 by caspases during anti-IgM-induced B-cell apoptosis. 1010 59

Caspase-3 is the major effector in apoptosis triggered by various stimuli. Previous studies demonstrated a significant increase in transcriptional activity of the caspase-3 gene during neuronal apoptosis. Recent findings suggest that differential expression of the caspase-3 gene may underlie the regulation of apoptotic susceptibility during brain development and after acute injury to the mature brain. We identified and cloned the rat caspase-3 gene promoter, determined its structure, and examined its regulation during a course of apoptosis in PC12 cells. Results demonstrate that this promoter lacks a TATA-box and contains a cluster of Sp1 elements and multiple transcription start sites. The first identified transcription start site is located 87-bp upstream from the first splicing site. A role of Sp1 elements in the regulation of caspase-3 promoter activity is demonstrated by the inhibition of Sp1 binding using mithramycin A. Results of deletion analysis show that an Ets-1-like element located between nucleotides -1646 and -1632 relative to the most extended transcription start site is necessary to achieve sustained transcriptional activity. Homology analysis revealed that the 5'-flanking region of the human caspase-3 gene exhibits significant similarity to a regulatory region of the rat gene.
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PMID:Identification and functional analysis of the rat caspase-3 gene promoter. 1177 55

We have isolated two overlapping genomic clones that contain the 5'-terminal portion of the human vacuolar H(+)-ATPase c subunit (ATP6L) gene. The sequence preceding the transcription initiation site, which is GC-rich, contains four GC boxes and one Oct1-binding site, but there is no TATA box or CCAAT box. In vivo footprint analysis in human cancer cells shows that two GC boxes and the Oct1-binding site are occupied by Sp1 and Oct1, respectively. We show here that treatment with anticancer agents enhances ATP6L expression. Although cisplatin did not induce ATP6L promoter activity, it altered ATP6L mRNA stability. On the other hand, the DNA topoisomerase II inhibitor, TAS-103, strongly induced promoter activity, and this effect was completely eradicated when a mutation was introduced into the Oct1-binding site. Treatment with TAS-103 increased the levels of both Sp1/Sp3 and Oct1 in nuclear extracts. Cooperative binding of Sp1 and Oct1 to the promoter is required for promoter activation by TAS-103. Incubation of a labeled oligonucleotide probe encompassing the -73/-68 GC box and -64/-57 Oct1-binding site with a nuclear extract from drug-treated KB cells yielded higher levels of the specific DNA-protein complex than an extract of untreated cells. Thus, the two transcription factors, Sp1 and Oct1 interact, in an adaptive response to DNA damage, by up-regulating expression of the vacuolar H(+)-ATPase genes. Furthermore, combination of the vacuolar H(+)-ATPase (V-ATPase) inhibitor, bafilomycin A1, with TAS-103 enhanced apoptosis of KB cells with an associated increase in caspase-3 activity. Our data suggest that the induction of V-ATPase expression is an anti-apoptotic defense, and V-ATPase inhibitors in combination with low-dose anticancer agents may provide a new therapeutic approach.
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PMID:Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents. 1213 27

IFNgamma is a pro-inflammatory cytokine that potentiates p53-independent apoptosis in a variety of cell types. STAT1 is the primary mediator of IFNgamma action. ZBP-89 is a transcription factor that binds to the G/C-rich elements and mediates p53-independent apoptosis. In this study, site-directed mutagenesis revealed that a G-rich element from +171 to +179 within the first intron of the STAT1 gene is critical for optimal STAT1 promoter activity. Electrophoretic mobility shift assays and promoter analysis revealed that ZBP-89 binds directly to this STAT1 G-rich element along with Sp1 and Sp3. Reduction of ZBP-89 with siRNA attenuated both basal and IFNgamma-induced STAT1 expression and subsequently diminished the activation of apoptotic markers, e.g. caspase-3 and PARP. Taken together, we conclude that ZBP-89 is required for constitutive STAT1 expression and in this way contributes to the ability of cells to be activated by IFNgamma.
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PMID:Transcription factor ZBP-89 is required for STAT1 constitutive expression. 1465 2

We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra-O-methyl nordihydroguaiaretic acid (M(4)N) and that M(4)N is likely responsible for causing growth arrest in M(4)N-treated transformed C3 cells. Here, we show that after M(4)N treatment and cell-cycle arrest, expression of the Sp1-dependent survivin gene, a member of the inhibitor of apoptosis family, is also suppressed, and the mitochondrial apoptotic pathway is activated. To confirm that inhibition of Cdc2 and survivin gene expression is necessary for M(4)N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M(4)N-treated cells. Cell division was transiently restored in the presence of M(4)N after transfection of an exogenous Cdc2 gene copy under the control of the Sp1-independent cytomegalovirus promoter. Caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. The results suggest that M(4)N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.
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PMID:Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. 1532 16

Although alpha-tocopherol is known as an essential micronutrient involved in various oxidative stress-related processes, its non-antioxidant activities have only been characterized in recent years. In this study, we reveal that (+)-alpha-tocopherol [RRR-alpha-tocopherol] enhances cellular susceptibility to both oxidative and non-oxidative apoptosis-inducing stimuli through up-regulation of caspase-3/CPP32 expression in several human cell lines. Exposure of (+)-alpha-tocopherol pretreated cells to known apoptosis-inducing stimuli, such as Fas, H(2)O(2), or etoposide, resulted in an increase in cellular apoptotsis. In addition, (+)-alpha-tocopherol also elevated the pro-caspase-3 protein level and mRNA expression in a time- and dose-dependent manner, while other tocopherol analogues showed no effect. Experiments using a GC-specific DNA binding agent, mithramycin A, and an electrophoretic mobility shift assay demonstrated that Sp1 might mediate the enhanced expression of caspase-3. Our results also confirmed that (+)-alpha-tocopherol promotes the expression, but not the activation, of caspase-3 in various human cell lines. These findings provide biological evidence showing that (+)-alpha-tocopherol can amplify the apoptotic response by up-regulating the expression of pro-caspase-3.
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PMID:Alpha-tocopherol-mediated caspase-3 up-regulation enhances susceptibility to apoptotic stimuli. 1600 47

TGF-beta signaling is indispensible for development of the nervous system since it regulates ontogenetic cell death. The recently identified TGF-beta-inducible zinc finger protein Tieg3/Klf11 belongs to the family of Sp1/Klf-like transcription factors and shares all structural and functional features with other Tieg proteins. Using the established TGF-beta-responsive oligodendroglial cell line OLI-neu, we analyzed the role of Tieg3/Klf11 in TGF-beta signaling. In this report, we show that Tieg3/Klf 11 mimics TGF-beta effects by inducing apoptotic cell death accompanied by activation of caspase-3. Moreover, we demonstrate that Tieg3/Klf11 enhances TGF-beta signaling by transcriptional repression of the inhibitory Smad7 and, thereby, disrupts the negative feedback loop of the TGF-beta signaling pathway. Loss of the N-terminal repression domains of Tieg3/Klf11 abrogates the pro-apoptotic nature of this transcription factor and abolishes the enhancement of Smad-mediated TGF-beta responses. In conclusion, we provide evidence that the recently identified transcription factor Tieg3/Klf11 is a downstream mediator of TGF-beta-induced apoptosis in the oligodendroglial cell line OLI-neu. Since other signaling molecules are able to initiate transcription of members of the Tieg family, the ability of Tieg3/Klf11 to modulate TGF-beta signaling by transcriptional inhibition of Smad7 might be an important clue for the understanding of the crosstalk between different signaling pathways.
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PMID:Tieg3/Klf11 induces apoptosis in OLI-neu cells and enhances the TGF-beta signaling pathway by transcriptional repression of Smad7. 1818 66

Recent studies indicate that gossypol possesses potent antitumor activities in vitro and in vivo. The nuclear factor-kappa B (NF-kappaB) plays an important role in tumor cell growth, proliferation, invasion, and survival. In this study, we investigated the effects and the molecular mechanisms of gossypol on NF-kappaB activation and NF-kappaB-related gene expression in human leukemia U937 cells. Treatment with concentrations of gossypol greater than 10 microM resulted in significant cell cytotoxicity and DNA fragmentation, indicative of apoptosis. Treatment with 10 microM gossypol also induced caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage, and resulted in the induction of apoptosis in approximately 20% of cells as determined by annexin-V staining 24h after treatment. Furthermore, gossypol exposure decreased the DNA-binding activity of NF-kappaB in a concentration-dependent manner. Treatment with gossypol also downregulated expression of NF-kappaB-regulated gene products, including inhibitor of apoptosis protein (IAP)-1, IAP-2, and X-linked IAP. Attenuation of NF-kappaB activity by pretreatment with PDTC, an NF-kappaB nuclear translocation inhibitor, significantly induced apoptosis in the presence of gossypol. Gossypol also suppressed NF-kappaB p65 mRNA accumulation, resulting in suppression of total NF-kappaB activity. This was associated with a downregulation of Sp1-binding activity, a transcription factor controlling p65 transcription. These results suggest that gossypol-induced apoptosis partially involves suppression of NF-kappaB activity.
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PMID:Gossypol suppresses NF-kappaB activity and NF-kappaB-related gene expression in human leukemia U937 cells. 1831 60

Caspase-3 is a cysteine protease that plays a central role in the execution of apoptosis induced by a wide variety of stimuli. However, little is known about the mechanisms involved in the regulation of caspase-3 gene transcription. This study was carried out to characterize the human caspase-3 promoter and to understand the mechanisms involved in the induction of caspase-3 gene expression in response to the anticancer drug cisplatin and p73. Caspase-3 gene expression was induced by treatment of cells with cisplatin, which also induced p73 protein in HeLa and K562 cells. The human caspase-3 promoter was cloned and characterized. p73beta strongly activated the caspase-3 promoter, whereas p73alpha showed less activation. Cisplatin treatment increased caspase-3 promoter activity. Basal and cisplatin-induced promoter activity was inhibited by the p73 inhibitor p73DD. Deletion analysis defined a minimal promoter of 120 base pairs, which showed good basal and p73beta-induced activity. The examination of the minimal promoter sequence showed several putative Sp1 sites, but no p53/p73 site. The caspase-3 promoter was activated by Sp1 in Sp1-deficient Drosophila SL-2 cells. Sp1-induced promoter activity was further enhanced by p73beta in SL-2 cells. Mutation of Sp1 sites in the minimal promoter resulted in a loss of basal and p73-induced promoter activity. These results show that caspase-3 gene transcription is induced by cisplatin, which is mediated partly by p73. We have identified p73 and Sp1 as activators of the caspase-3 promoter. Sp1-like sequences in the minimal promoter not only sustain basal promoter activity, but also mediate p73-induced activation of the promoter.
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PMID:Sp1-like sequences mediate human caspase-3 promoter activation by p73 and cisplatin. 1838 75

The androgen receptor cross-talks with transforming growth factor-beta (TGF-beta) through mechanisms that remain poorly understood. Here we provide strong evidence that 5alpha-dihydrotestosterone (DHT) intercepts the ability of prostate epithelial cells to undergo TGF-beta-induced apoptosis, and present a new model for this androgenic effect. We report that DHT decreases the level of TGF-beta receptor II (TbetaRII) through a transcriptional mechanism, leading to suppression of the ability of TGF-beta to down-regulate expression of Bcl-xL and cyclin Ds, activate caspase-3, and induce apoptosis. Promoter analysis, DNA pulldown, and electrophoretic mobility shift assays support that transcriptional down-regulation of TbetaRII by DHT occurs through Sp1/Sp3 response elements, with the binding of Sp1 to the TbetaRII promoter being suppressed by DHT, largely driven by loss of Sp1 protein and/or activity. These results provide fresh insight on the mechanism of growth control by androgens and the progression of prostate cancer to androgen independence. [Cancer Res 2008;68(19):8173-82].
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PMID:Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II. 1882 77


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