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 human disease xeroderma pigmentosum (XP) involves DNA repair and replication deficiencies that predispose homozygous individuals to a 1000-fold increase in nonmelanoma and melanoma skin cancers. Two major forms of XP are known with different biochemical defects: one form lacks nucleotide excision repair (NER); the other lacks the capacity to replicate damaged DNA. Since the clinical symptoms of both kinds of patients are almost the same, the different cellular defects must be reconciled with common clinical outcomes. An additional question among the NER defective patients is how to reconcile widely different skin and central nervous system symptoms with mutations in the same biochemical pathway. XP involves seven genes of the NER system (XPA through G). The XPA gene codes for a protein that is central to NER and binds to a variety of UV light and chemical damage to DNA. It also acts as a nucleation center for other repair proteins to attach and carry out excision and replacement synthesis. Mutations in XPA that are within the DNA binding site produce more severe CNS disorders, than mutations in the C-terminal region of the protein that interacts with the TFIIH complex. In contrast, mutations in two members of the TFIIH complex, the XPB and XPD genes are generally very severe with both skin and CNS disorders. Missense mutations within the helicase regions of these genes are associated with DNA repair deficiencies and XPD; mutations elsewhere in these genes are correlated with symptoms of XP and Cockayne syndrome and trichothiodystrophy. This raises the question whether the CNS disorders of XPA, XPB, and XPD patients are similar, or whether a careful clinical evaluation might reveal different mechanisms of development. The XP variant lacks the capacity to replicate damaged DNA due to mutations in hRad30, a damage-specific polymerase eta. The phenotype of XP variant cells becomes unstable and the cells become much more UV-sensitive when they are transformed by methods that inactivate p53. On a p53 negative background, the induction of recombination between sister chromatids occurs much more extensively than in normal cells, and we have evidence that DNA double strand breaks which trigger an apoptotic pathway involving caspase-3 are involved. The pathway for UV carcinogenesis may be the same for all XP patients if the ultimate cause of genomic instability is an increase in replication of damaged DNA by the error-prone polymerase zeta. The presence of unrepaired damage in the NER defective groups of XP would present more substrate for the error-prone system leading to increased mutation rates. The absence of pol eta would require cells to use the error-prone pol zeta pathway, also increasing mutation rates from UV damage. A common pathway for increased mutagenesis therefore underlies both forms of XP.
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PMID:Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmentosum. 1069 59

Adeno-associated virus (AAV) type 2 Rep78 is a multifunctional protein required for AAV DNA replication, integration, and gene regulation. The biochemical activities of Rep78 have been described, but the effects of Rep proteins on the cell have not been characterized. We have analyzed Rep-mediated cytotoxicity. We demonstrated that Rep78 expression is sufficient to induce cell death and disruption of the cell cycle. Cell death was found to be mediated by apoptosis. Rep78 expression resulted in the activation of caspase-3, a terminal caspase directly involved in the execution of cell death. A peptidic inhibitor of caspase-3, Z-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), abrogated Rep78-induced apoptosis, indicating that Rep78-mediated apoptosis is caspase-3 dependent. Rep78 induced apoptosis in wild-type p53-containing human embryonal carcinoma NT-2 cells and in p53-null promyelocytic human HL-60 cells, indicating that at least one pathway of Rep78-induced apoptosis is p53 independent. Apoptosis was shown to occur during the G(1) and early S phases of the cell cycle. By analyzing the effects of Rep78 mutations on cell viability, the cause of cell death was attributed in part to two biochemical activities of Rep78, DNA binding and ATPase/helicase activity. The endonuclease activity of Rep78 did not contribute to apoptosis induction.
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PMID:Adeno-associated virus type 2 Rep78 induces apoptosis through caspase activation independently of p53. 1100 Feb 13

Bloom syndrome (BS) is an autosomal recessive disorder characterized by a high incidence of cancer and genomic instability. BLM, the protein defective in BS, is a RECQ-like helicase that is presumed to function in mammalian DNA replication, recombination, or repair. We show here that BLM, but not the related RECQ-like helicase WRN, is rapidly cleaved in cells undergoing apoptosis. BLM was cleaved to 47- and 110-kDa major fragments, with kinetics similar to the apoptotic cleavage of poly(A)DP-ribose polymerase. BLM cleavage was prevented by a caspase 3 inhibitor and did not occur in caspase 3-deficient cells. Moreover, recombinant BLM was cleaved to 47- and 110-kDa fragments by caspase 3, but not caspase 6, in vitro. The caspase 3 recognition sequence (412)TEVD(415) was verified by mutating aspartate 415 to glycine and showing that this mutation rendered BLM resistant to caspase 3 cleavage. Cleavage did not abolish the BLM helicase activity but abolished BLM nuclear foci and the association of BLM with condensed DNA and the insoluble matrix. The results suggest that BLM, but not WRN, is an early selected target during the execution of apoptosis.
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PMID:Selective cleavage of BLM, the bloom syndrome protein, during apoptotic cell death. 3327 4

In higher eukaryotes, the integration of signals triggered in response to certain types of stress can result in programmed cell death. Central to these events is the sequential activation of a cascade of proteinases known as caspases. The final activated effector caspases of this cascade digest a number of cellular proteins, in some cases increasing their enzymatic activity, in others destroying their function. Of the proteins shown to be targets for caspase-mediated proteolysis, a surprisingly large proportion are proteins involved in the signalling or repair of DNA damage. Here we investigate whether BLM, the product of the gene mutated in Bloom's syndrome, a human autosomal disease characterised by cancer predisposition and sunlight sensitivity, is cleaved during apoptosis. BLM interacts with topoisomerase IIIalpha and has been proposed to play an important role in maintaining genomic integrity through its roles in DNA repair and replication. We show that BLM is cleaved during apoptosis by caspase-3 and reveal that the main cleavage site is located at the junction between the N-terminal and central helicase domains of BLM. Proteolytic cleavage by caspase-3 produces a 120 kDa fragment, which contains the intact helicase domain and three smaller fragments, the relative amounts of which depend on time of incubation with caspase-3. The 120 kDa fragment retains the helicase activity of the intact BLM protein. However, its interaction with topoisomerase IIIalpha is severely impaired. Since the BLM-topoisomerase interaction is believed to be necessary for many of the replication and recombination functions of BLM, we suggest that caspase-3 cleavage of BLM could alter the localisation and/or function of BLM and that these changes may be important in the process of apoptosis.
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PMID:Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha. 1147 Aug 74

Apoptotic cell death is characterized by several morphological nuclear changes, such as chromatin condensation and extensive fragmentation of chromosomal DNA. These alterations are primarily triggered through the activation of caspases, which subsequently cleave nuclear substrates. Caspase-3 induces processing of Acinus, which leads to chromatin condensation. DNA fragmentation is dependent on the DNase CAD, which is released from its inhibitor, ICAD, upon cleavage by caspase-3. DNA degradation is also induced by AIF and endonuclease G, which are both released from mitochondria upon death stimuli but do not require prior processing by caspases for their DNase activity. Here we report the identification of a widely expressed helicase designated Helicard, which contains two N-terminal CARD domains and a C-terminal helicase domain. Upon apoptotic stimuli, Helicard is cleaved by caspases, thereby separating the CARD domains from the helicase domain. While Helicard localizes in the cytoplasm, the helicase-containing fragment is found in the nucleus. Helicard accelerates Fas ligand-mediated DNA degradation, whereas a noncleavable or a helicase-dead Helicard mutant does not, implicating Helicard in the nuclear remodeling occurring during apoptosis.
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PMID:Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. 1201 21

The West Nile Virus (WNV) non-structural proteins 2B and 3 (NS2B-NS3) constitute the proteolytic complex that mediates the cleavage and processing of the viral polyprotein. NS3 recruits NS2B and NS5 proteins to direct protease and replication activities. In an effort to investigate the biology of the viral protease, we cloned cDNA encoding the NS2B-NS3 proteolytic complex from brain tissue of a WNV-infected dead crow, collected from the Lower Merion area (Merion strain). Expression of the NS2B-NS3 gene cassette induced apoptosis within 48 h of transfection. Electron microscopic analysis of NS2B-NS3-transfected cells revealed ultra-structural changes that are typical of apoptotic cells including membrane blebbing, nuclear disintegration and cytoplasmic vacuolations. The role of NS3 or NS2B in contributing to host cell apoptosis was examined. NS3 alone triggers the apoptotic pathways involving caspases-8 and -3. Experimental results from the use of caspase-specific inhibitors and caspase-8 siRNA demonstrated that the activation of caspase-8 was essential to initiate apoptotic signaling in NS3-expressing cells. Downstream of caspase-3 activation, we observed nuclear membrane ruptures and cleavage of the DNA-repair enzyme, PARP in NS3-expressing cells. Nuclear herniations due to NS3 expression were absent in the cells treated with a caspase-3 inhibitor. Expression of protease and helicase domains themselves was sufficient to trigger apoptosis generating insight into the apoptotic pathways triggered by NS3 from WNV.
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PMID:Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway. 1624 74

Gonadotropin-regulated testicular helicase (GRTH)/DDX25 is an essential post-transcriptional regulator of spermatogenesis. In GRTH null mice severe apoptosis was observed in spermatocytes entering the metaphase of meiosis. Pro- and anti-apoptotic factors were found to be under GRTH regulation in comparative studies of spermatocytes from wild type and GRTH(-/-) knock-out (KO) mice. KO mice displayed decreased levels of Bcl-2 and Bcl-xL (anti-apoptotic factors), an increase in Bid, Bak, and Bad (pro-apoptotic), reduced phospho-Bad, and release of cytochrome c. Also, an increase on Smac, a competitor of inhibitor apoptotic proteins that release caspases, was observed. These changes caused an increase in cleavage of caspases 9 and 3, activation of caspase 3 and increases in cleavage products of PARP. The half-life of caspase 3 transcripts was markedly increased in KO, indicating that GRTH had a negative role on its mRNA stability. IkappaBalpha, which sequesters NF-kappaB from its transcriptional activation of pro-apoptotic genes, was highly elevated in KO, and its phospho-form, which promotes its dissociation, was reduced. The increase of HDAC1 and abolition of p300 expression in KO indicated a nuclear action of GRTH on the NF-kappaB-mediated transcription of anti-apoptotic genes. It also regulates the associated death domain pathway and caspase 8-mediated events. GRTH-mediated apoptotic regulation was further indicated by its selective binding to pro- and anti-apoptotic mRNAs. These studies have demonstrated that GRTH, as a component of mRNP particles, acts as a negative regulator of the tumor necrosis factor receptor 1 and caspase pathways and promotes NF-kappaB function to control apoptosis in spermatocytes of adult mice.
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PMID:Gonadotropin-regulated testicular helicase (DDX25), an essential regulator of spermatogenesis, prevents testicular germ cell apoptosis. 1843 Jul 33

Hormone-refractory prostate cancer is one of the intractable human cancers in the world. Here, we examined the direct tumor-killing activity of inactivated Sendai virus particle [hemagglutinating virus of Japan envelope (HVJ-E)] through induction of Type I interferon (IFN) in the hormone-resistant human prostate cancer cell lines PC3 and DU145. Preferential binding of HVJ-E to PC3 and DU145 over hormone-sensitive prostate cancer cell and normal prostate epithelium was observed, resulting in a number of fused cells. After HVJ-E treatment, a number of IFN-related genes were up-regulated, resulting in Type I IFN production in PC3 cells. Then, retinoic acid-inducible gene-I (RIG-I) helicase which activates Type I IFN expression after Sendai virus infection was up-regulated in cancer cells after HVJ-E treatment. Produced IFN-alpha and -beta enhanced caspase 8 expression via Janus kinases/Signal Transducers and Activators of Transcription pathway, activated caspase 3 and induced apoptosis in cancer cells. When HVJ-E was directly injected into a mass of PC3 tumor cells in SCID (severe combined immunodeficiency) mice, a marked reduction in the bulk of each tumor mass was observed and 85% of the mice became tumor-free. Although co-injection of an anti-asialo GM1 antibody with HVJ-E into each tumor mass slightly attenuated the tumor suppressive activity of HVJ-E, significant suppression of tumor growth was observed even in the presence of anti-asialo GM1 antibody. This suggests that natural killer cell activation made small contribution to tumor regression following HVJ-E treatment in hormone-resistant prostate cancer model in vivo. Thus, HVJ-E effectively targets hormone-resistant prostate cancer by inducing apoptosis in tumor cells, as well as activating anti-tumor immunity.
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PMID:Efficient eradication of hormone-resistant human prostate cancers by inactivated Sendai virus particle. 1917 82

Dicer plays a key role in the biogenesis of microRNAs and small interfering RNAs, which control the coordinated expression of multiple of genes during follicle development. In this study, the cDNAs encoding two Dicer isoforms (gDicer-a and gDicer-b, respectively) were isolated and cloned from goose ovary using RT-PCR. This is the first time a new Dicer splice variant has been characterized at the molecular level in vertebrates. Sequence analysis indicated that both of the two isoforms consist of seven conserved functional domains, where gDicer-b lacks a linker sequence between DEAD box and helicase C domain composed of 158 amino acids. Each domain of gDicer-a/gDicer-b showed higher than 89.5% identity to corresponding domain of Dicers from chicken, human, and mouse. The ubiquity of transcripts of gDicer-a/gDicer-b was found in all tested tissues by real time PCR with the pituitary, oviduct, and hypothalamus being the predominant site of expression of gDicer-a. A similar expression profile of the gDicer-a/gDicer-b mRNAs was found during follicle development. The abrupt changes in transcripts of gDicer in 2-4mm, 9-10mm, F5, and F1 follicles support its participation in the process of follicle recruitment, selection, dominance, and ovulation. However, high mRNA levels of gDicer-b and caspase-3 were detectable in atretic and post-ovulatory follicles, where expression of gDicer-a was considerably low. These findings suggest that gDicer is required for follicle development, and structural differences in the helicase domain of two gDicer isoforms might contribute to their different roles in controlling granulosa cell apoptosis.
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PMID:Molecular characterization, tissue distribution, and expression of two ovarian Dicer isoforms during follicle development in goose (Anser cygnoides). 2446 10

Fanconi anemia (FA) is a rare genome instability syndrome with progressive bone marrow failure and cancer susceptibility. FANCJ is one of 17 genes mutated in FA-patients, comprises a DNA helicase that is vital for properly maintaining genomic stability and is known to function in the FA-BRCA DNA repair pathway. While exact role(s) of FANCJ in this repair process is yet to be determined, it is known to interact with primary effector FANCD2. However, FANCJ is not required for FANCD2 activation but is important for its ability to fully respond to DNA damage. In this report, we determined that transient depletion of FANCJ adversely affects stability of FANCD2 and its co-regulator FANCI in multiple cell lines. Loss of FANCJ does not significantly alter cell cycle progression or FANCD2 transcription. However, in the absence of FANCJ, the majority of FANCD2 is degraded by both the proteasome and Caspase-3 dependent mechanism. FANCJ is capable of complexing with and stabilizing FANCD2 even in the absence of a functional helicase domain. Furthermore, our data demonstrate that FANCJ is important for FANCD2 stability and proper activation of DNA damage responses to replication blocks induced by hydroxyurea.
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PMID:FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation. 2633 24


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