Functional Characterization of DNase X, a Novel Endonuclease Expressed in Muscle Cells

Łos, Marek; Neubüser, Dagmar; Coy, Johannes F.; Mozoluk, Malgorzata; Poustka, and Annemarie; Schulze‐Osthoff, Klaus

doi:10.1021/bi000158w

Cited by 44 publications

(40 citation statements)

References 37 publications

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“…Genes such as adenosine A3 receptor, which inhibits apoptosis at low ligand concentrations, and CD40, a member of the TNF superfamily that induces apoptosis, are differentially expressed, resulting in the increased induction of apoptosis (21, 27, 34, 55, 62). These changes are accompanied by the up-regulation of DNase X and the down-regulation of RNA polymerase II SIII p15 subunit, which may induce intrinsic apoptosis through DNA degradation and defective transcription, respectively (37,51). On the other hand, DNase X could potentially be one of the targets for apoptosis-inducing factor, which triggers nuclear apoptosis after dissipation of the mitochondrial transmembrane potential, an event that is crucial to apoptosis (14).…”

Section: Necrosis-associated Genes In Glioblastomamentioning

confidence: 99%

Identification of Necrosis-Associated Genes in Glioblastoma by cDNA Microarray Analysis

Raza¹,

Fuller²,

Rhee³

et al. 2004

Clinical Cancer Research

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Purpose: In the field of cancer research, there has been a paucity of interest in necrosis, whereas studies focusing on apoptosis abound. In neuro-oncology, this is particularly surprising because of the importance of necrosis as a hallmark of glioblastoma (GBM), the most malignant and most common primary brain tumor, and the fact that the degree of necrosis has been shown to be inversely related to patient survival. It is therefore of considerable interest and importance to identify genes and gene products related to necrosis formation.Experimental Design: We used a nylon cDNA microarray to analyze mRNA expression of 588 universal cellular genes in 15 surgically resected human GBM samples with varying degrees of necrosis. Gene expression was correlated with the degree of necrosis using rank correlation coefficients. The expression of identified genes was compared with their expression in tissue samples from 5 anaplastic astrocytomas (AAs). Immunostaining was used to determine whether genes showing the most positive correlation with necrosis were increasingly expressed in tumor tissues, as grade of necrosis increased.Results: The hybridization results indicated that 26 genes showed significant correlation with the amount of necrosis. All 26 genes had functions associated with either Ras, Akt, tumor necrosis factor ␣, nuclear factor B, apoptosis, procoagulation, or hypoxia. Nine genes were positively correlated with necrosis grade, and 17 genes were negatively correlated with necrosis grade. There were significant differences in the median expression levels of 3 of the 26 genes between grade III necrosis GBM and anaplastic astrocytoma (AA) samples; all but 1 of the genes had elevated expression when comparing necrosis grade III with AA samples. Two factors, the ephrin type A receptor 1 and the prostaglandin E 2 receptor EP4 subtype, not previously considered in this context, were highlighted because of their particularly high (positive) correlation coefficients; immunostaining showed the products of these two genes to be localized in perinecrotic and necrotic regions and to be overexpressed in grade III GBMs, but not AAs. These two molecules also showed significant correlation with survival of GBM patients (P ‫؍‬ 0.0034) in a combined model. Conclusions:The application of cDNA expression microarray analysis has identified specific genes and patterns of gene expression that may help elucidate the molecular basis of necrogenesis in GBM. Additional studies will be required to further investigate and confirm these findings.

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Section: Necrosis-associated Genes In Glioblastomamentioning

confidence: 99%

Identification of Necrosis-Associated Genes in Glioblastoma by cDNA Microarray Analysis

Raza¹,

Fuller²,

Rhee³

et al. 2004

Clinical Cancer Research

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“…After washing with cold PBS, the pellet was resuspended in 400 ml RNase (1 mg/ml) and incubated for 1 h at 48C. After addition of 20 ml of propidium iodide (2 mg/ml, Sigma) hypodiploid nuclei were measured by¯ow cytometry as described Los et al, 2000). Nuclei to the left of the 2N peak containing hypodiploid DNA were considered as apoptotic.…”

Section: Measurement Of Cell Deathmentioning

confidence: 99%

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

et al. 2001

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The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis

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“…8 Although no clear in vivo relevance has been provided yet, other factors being involved in nuclear DNA fragmentation during the apoptotic process have been described. 9,10 In our search for proteins that are released from mitochondria after an apoptotic stimulus, we identified endonuclease G as such a candidate, using an in vitro reconstitution system with purified recombinant tBid or apoptotic cytosol from Fas-treated L929sAhFas cells on isolated mitochondria. Endonuclease G, a mitochondrial nuclease that has been suggested to play a role in mitochondrial DNA replication, 11 was clearly released together with cytochrome c. When incubated with purified nuclei, the tBid-induced mitochondrial supernatant could evoke DNA degradation.…”

Section: Introductionmentioning

confidence: 99%

Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation

et al. 2001

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A hallmark of apoptosis is the fragmentation of nuclear DNA. Although this activity involves the caspase-3-dependent DNAse CAD (caspase-activated DNAse), evidence exists that DNA fragmentation can occur independently of caspase activity. Here we report on the ability of truncated Bid (tBid) to induce the release of a DNAse activity from mitochondria. This DNAse activity was identified by mass spectrometry as endonuclease G, an abundant 30 kDa protein released from mitochondria under apoptotic conditions. No tBid-induced endonuclease G release could be observed in mitochondria from Bcl-2-transgenic mice. The in vivo occurrence of endonuclease G release from mitochondria during apoptosis was confirmed in the liver from mice injected with agonistic anti-Fas antibody and is completely prevented in Bcl-2 transgenic mice. These data indicate that endonuclease G may be involved in CAD-independent DNA fragmentation during cell death pathways in which truncated Bid is

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Functional Characterization of DNase X, a Novel Endonuclease Expressed in Muscle Cells

Cited by 44 publications

References 37 publications

Identification of Necrosis-Associated Genes in Glioblastoma by cDNA Microarray Analysis

Identification of Necrosis-Associated Genes in Glioblastoma by cDNA Microarray Analysis

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells

Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation

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