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)

The spermine analogue N(1),N(11)-diethylnorspermine (DENSPM) efficiently depletes the cellular pools of putrescine, spermidine and spermine by down-regulating the activity of the polyamine biosynthetic enzymes and up-regulating the activity of the catabolic enzyme spermidine/ spermine N(1)-acetyltransferase (SSAT). In the breast cancer cell line L56Br-C1, treatment with 10 microm DENSPM induced SSAT activity 60 and 240-fold at 24 and 48 h after seeding, respectively, which resulted in polyamine depletion. Cell proliferation appeared to be totally inhibited and within 48 h of treatment, there was an extensive apoptotic response. Fifty percent of the cells were found in the sub-G(1) region, as determined by flow cytometry, and the presence of apoptotic nuclei was morphologically assessed by fluorescence microscopy. Caspase-3 and caspase-9 activities were significantly elevated 24 h after seeding. At 48 h after seeding, caspase-3 and caspase-9 activities were further elevated and at this time point a significant activation of caspase-8 was also found. The DENSPM-induced cell death was dependent on the activation of the caspases as it was inhibited by the general caspase inhibitor Z-Val-Ala-Asp fluoromethyl ketone. The results are discussed in the light of the L56Br-C1 cells containing mutated BRCA1 and p53, two genes involved in DNA repair.
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PMID:Rapid caspase-dependent cell death in cultured human breast cancer cells induced by the polyamine analogue N(1),N(11)-diethylnorspermine. 1184 6

The breast cancer suppressor protein, BRCA1 plays an important role in mediating cell cycle arrest, apoptosis and DNA responses to DNA damage signals. In this study, we show that BRCA1 level is downregulated during UV-induced apoptosis by caspase-3 mediated cleavage. Cleavage of BRCA1 by caspase-3 produced a fragment that contained the C-terminal of the molecule. Accordingly, treatment of cells with caspase-3 inhibitor or mutation of a specific caspase-3 cleavage site (DLLD) at amino acid 1151-1154 of BRCA1 abolished cleavage and consequential accumulation of the BRCA1 C-terminal fragment. Whereas expression of the non-cleavable BRCA1 (D/A 1154) mutant conferred the resistance phenotype to UV-induced cell death, expression of the cleaved BRCA1 C-terminus induced cell death in the absence of UV. Examination of the mechanism of C-terminus-induced cell death revealed that the cleaved fragment triggers the apoptotic response through activation of BRCA1 downstream effectors, GADD45 and JNK. Altogether, results of our study demonstrate a functional role for caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis.
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PMID:Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis. 1214 54

BACKGROUND: The frequently occurring 185delAG mutation occurs in the amino-terminal zinc RING domain of the breast and ovarian cancer susceptibility gene, BRCA1. We sought to determine differential cell viability and apoptotic response of human ovarian surface epithelial cells with and without the 185delAG mutation. RESULTS: BRCA1wt and BRCA1+ cells were treated with staurosporine. Cell proliferation assays showed BRCA1wt cells grew to a greater extent compared to BRCA1+ cells. Trypan blue exclusion assays confirmed this observation. Western immunoblot analysis revealed that caspase 3 levels were higher after staurosporine treatment in BRCA1+ cells than in wild type cells, while full length DNA Fragmentation Factor 45 levels were lower in BRCA1+ cells. While there was no significant difference in levels of excision repair cross complementing protein1 (ERCC1) with BRCA1 status, BRCA1+ cells demonstrated cleavage of polyribose ADP polymerase (PARP) before wild type cells. CONCLUSIONS: Disruption of the BRCA1 RING domain caused altered cell viability and caspase-dependent apoptotic response after chemotoxic stress.
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PMID:BRCA1 Zinc RING Finger Domain Disruption Alters Caspase Response in Ovarian Surface Epithelial Cells. 1223 76

We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10-1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G(2)/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult.
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PMID:BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. 1455 7

Fusion between nonsynchronized cells leads to the formation of heterokarya which transiently activate Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 and enter the prophase of the cell cycle, where they arrest due to a loss of Cdk1/cyclin B1 activity, activate p53, disorganize centrosomes, and undergo apoptosis. Here, we show that the down regulation of Cdk1/cyclin B is secondary to the activation of the DNA structure checkpoint kinase Chk2. Thus, syncytia generated by the fusion of asynchronous HeLa cells contain elevated levels of active Chk2 but not Chk1. Chk2 bearing the activating phosphorylation on threonine-68 accumulates in BRCA1 nuclear bodies when the cells arrest at the G2/M boundary. Inhibition of Chk2 by transfection of a dominant-negative Chk2 mutant or a chemical inhibitor, debromohymenialdesine, stabilizes centrosomes, maintains high cyclin B1 levels, and allows for a prolonged activation of Cdk1. Under these conditions, multinuclear HeLa syncytia do not arrest at the G2/M boundary and rather enter mitotis and subsequently die during the metaphase of the cell cycle. This mitotic catastrophe is associated with the activation of the pro-apoptotic caspase-3. Inhibition of caspases allows the cells to go beyond the metaphase arrest, indicating that apoptosis is responsible for cell death by mitotic catastrophe. In another, completely different model of mitotic catastrophe, namely 14.3.3 sigma-deficient HCT116 colon carcinoma cells treated with doxorubicin, Chk2 activation was also found to be deficient as compared to 14.3.3 sigma-sufficient controls. Inhibition of Chk2 again facilitated the induction of mitotic catastrophe in HCT116 wild-type cells. In conclusion, a conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe, provided that the checkpoint kinase Chk2 is inhibited. Inhibition of Chk2 thus can sensitize proliferating cells to chemotherapy-induced apoptosis.
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PMID:The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. 1504 74

The BRCA1-binding RING-finger domain protein BARD1 may act conjointly with BRCA1 in DNA repair and in ubiquitination, but it may also induce apoptosis in a BRCA1-independent manner. In this study, we have investigated BARD1 expression during spermatogenesis. In contrast with BRCA1, which is expressed only in meiotic spermatocytes and early round spermatids, BARD1 is expressed during all stages of spermatogenesis. However, while spermatogonia expressed full-length BARD1 mRNA, later stages of spermatocyte precursors express predominantly a novel, shorter splice form BARD1beta. BARD1beta lacks the BRCA1-interacting RING finger but maintains its proapoptotic activity. Consistently, BRCA1 can counteract the proapoptotic activity of full-length BARD1 but not of BARD1beta. Several lines of evidence suggest that BARD1 is involved in proapoptotic signaling in testis: i) both BARD1 isoforms are mostly found in cells that stain positive for TUNEL, Bax, and activated caspase 3; ii) BARD1beta, capable of inducing apoptosis even in the presence of BRCA1, is specifically expressed in BRCA1-positive later stages of spermatogenesis; iii) antiapoptotic hormonal stimulation leads to BARD1 downregulation; and iv) BARD1 expression is associated with human pathologies causing sterility due to increased germ cell death. Our data suggest that full-length BARD1 might be involved in apoptotic control in spermatogonia and primary spermatocytes, while a switch to the BRCA1-independent BARD1beta might be necessary to induce apoptosis in BRCA1-expressing meiotic spermatocytes and early round spermatids.
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PMID:BARD1 expression during spermatogenesis is associated with apoptosis and hormonally regulated. 1524 Apr 24

BRCA1 mutations have long been associated with altered apoptosis. We have recently reported that caspase 3 activation is increased in human ovarian surface epithelial (OSE) cells expressing a germline N-terminal BRCA1 185delAG mutation. Here, we report increased caspase 3 activity in 185delAG OSE cells associated with decreased expression of cIAP-1 and X-linked inhibitor of apoptosis (XIAP), and decreased ubiquitination of caspase 3. Overexpression of XIAP restored active caspase 3 ubiquitination and lowered levels of caspase 3 activity. Further, the BRCA1 185delAG mutation was associated with reduced levels of phosphorylated Akt1. Transfection with activated Akt1 led to increased cIAP-1 and XIAP levels similar to that seen in BRCA1 185delAG cell lines. Taken together, these data suggest a direct link between the BRCA1 185delAG mutation and alterations in the caspase-mediated apoptotic pathway.
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PMID:BRCA1 185delAG mutation inhibits Akt-dependent, IAP-mediated caspase 3 inactivation in human ovarian surface epithelial cells. 1524 57

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

Apoptosis is implemented by death machinery that involves the caspase family of proteins, under the condition of a variety of stresses. Previous studies have shown that mouse embryonic stem cells deficient for caspase-3 are resistant to UV-induced apoptosis and that the active form of caspase-3 translocates to the nucleus. It has also been shown that the breast cancer tumor suppressor, BRCA1, is phosphorylated on Ser1423 and Ser1524 by the ataxia telangiectasia mutated-related kinase (ATR) after UV damage. Here, we show that activation of caspase-3 by UV is abrogated in BRCA1-mutated SNU251 and HCC1937 cells but was restored by reexpressing wild-type (wt) BRCA1, but not phosphorylation-deficient BRCA1Ser1423Ala/Ser1524Ala (BRCA1(S1423/1524A)). In SNU251 cells expressing BRCA1(S1423/1524A), the inhibitory interaction between X-linked inhibitor of apoptosis protein (XIAP) and caspase-9 remains intact after UV, compared with cells expressing wt BRCA1. We determined that XIAP and BRCA1 interact and upon phosphorylation this complex is disrupted. Nuclear translocation of active caspase-3 is detected only when wt BRCA1 is reexpressed. Consistent with this, Rad21, a known substrate of caspase-3, is cleaved only when wt BRCA1 is expressed in vivo. These results propose a model that inhibition of BRCA1 phosphorylation leads to the abrogation of a specific form of apoptosis that is mediated by caspase-3.
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PMID:BRCA1 phosphorylation regulates caspase-3 activation in UV-induced apoptosis. 1632 7

More than a decade has passed since BRCA1, breast cancer tumor suppressor 1, was isolated by reverse genetics in 1994. Its molecular structure and potential function have been extensively studied; both mouse genetics and a cell culture system revealed that BRCA1 is a 220,240 kD nuclear phosphoprotein, it regulates transcription, its loss leads to genome instability and in turn, cell transformation. Significantly, DNA checkpoint associated kinases have been shown to phosphorylate specific residues of BRCA1 under conditions of DNA damage, making cells sensitive or resistant to various stresses. Our recent findings support the notion that UV induced phosphorylation of particular residues of the protein is crucial for activation of caspase 3. This article will focus on the BRCA1 kinases, the identification of the phosphorylation residues, and the biological consequences of BRCA1's phosphorylation for regulation of cell proliferation.
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PMID:BRCA1 phosphorylation: biological consequences. 1672 Oct 40


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