Identification of Regulatory and Catalytic Domains in the Apoptosis Nuclease DFF40/CAD

Inohara, Naohiro; Koseki, Takeyoshi; Chen, Shu; Benedict, Mary A.; Núñez, Gabriel

doi:10.1074/jbc.274.1.270

Cited by 66 publications

(57 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As described by Gu et al (1999), central domain of DFF45 (amino-acid residues 101-180) is required for the interaction with DFF40 and DFF45 can assist in the synthesis of highly active DFF40. In addition, the catalytic domain of DFF40 is located in its COOH-terminal region (aminoacid residues 290-345) (Inohara et al, 1999). As our mutation searches revealed that NB-C201 cells express wild-type DFF40 (data not shown), it is likely that CDDP-mediated nuclear fragmentation might be regulated in a DFF45-but not in a DFF40-dependent manner.…”

mentioning

confidence: 90%

DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells

et al. 2007

View full text Add to dashboard Cite

We have previously defined a homozygously deleted region at chromosome 1p36.2-p36.3 in human neuroblastoma cell lines, NB-1 and NB-C201, and identified six genes including DFF45/ICAD within this region. In this study, we found that NB-C201 cells are much more resistant to various genotoxic stresses such as cisplatin (CDDP) than CHP134 and SH-SY5Y cells that do not have the homozygous deletion. To examine a role(s) of DFF45 in the regulation of apoptosis in response to CDDP, we have established stably DFF45-expressing NB-C201 cell clones (DFF45-1 and DFF45-3) and a control cell clone (NB-C201-C) using a retrovirus-mediated gene transfer. In contrast to NB-C201-C cells, DFF45-3 cells displayed apoptotic nuclear fragmentation in response to CDDP. Although CDDP-induced proteolytic cleavage of procaspase-3 and DFF45 in DFF45-3 cells, we could not detect a typical apoptotic DNA fragmentation. Additionally, deletion analysis revealed that C-terminal region of DFF45 is required for inducing nuclear fragmentation. Unexpectedly, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that DFF45 has undetectable effect on CDDP sensitivity of NB-C201 cells. Taken together, our present results suggest that DFF45/DFF40 system may be sufficient for CDDP-induced nuclear fragmentation but not DNA cleavage.

show abstract

mentioning

confidence: 90%

DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells

et al. 2007

View full text Add to dashboard Cite

show abstract

“…In the late 1990s, caspase-3 was found to cleave a novel cytoplasmic protein termed ICAD (for inhibitor of caspase-activated DNase), which is homologous to the DNA fragmentation factor-45 (DFF45), originally described in HeLa cells Liu et al, 1998;Sakahira et al, 1998;Inohara et al, 1999;Sakahira et al, 1999). ICAD normally forms a heterodimer with and inhibits the actions of CAD (or DFF40), the first caspase-activated DNase that is responsible for the DNA fragmentation pattern that is a hallmark of apoptosis.…”

Section: Therapeutic Interventions: Delivery Of Anti-apoptotic Genes mentioning

confidence: 99%

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Springer¹

2002

BMB Reports

View full text Add to dashboard Cite

Apoptotic cell death is a fundamental and highly regulated biological process in which a cell is instructed to actively participate in its own demise. This process of cellular suicide is activated by developmental and environmental cues and normally plays an essential role in eliminating superfluous, damaged, and senescent cells of many tissue types. In recent years, a number of experimental studies have provided evidence of widespread neuronal and glial apoptosis following injury to the central nervous system (CNS). These studies indicate that injury-induced apoptosis can be detected from hours to days following injury and may contribute to neurological dysfunction. Given these findings, understanding the biochemical signaling events controlling apoptosis is a first step towards developing therapeutic agents that target this cell death process. This review will focus on molecular cell death pathways that are responsible for generating the apoptotic phenotype. It will also summarize what is currently known about the apoptotic signals that are activated in the injured CNS, and what potential strategies might be pursued to reduce this cell death process as a means to promote functional recovery.

show abstract

“…The endonuclease can still remain inhibited by the ICAD D1 domain, which interacts with the regulatory domain of CAD thus preventing its proper activation. It has been proposed that the residues of the EDG loop of the CAD CIDE-N domain are important for the nuclease activity, possibly by interacting directly with the CAD catalytic domain [23,24]. The fragments described here could displace the interaction between the ICAD D1 domain and CAD, allowing the regulatory domain of CAD available for the interaction with the catalytic domain.…”

Section: Discussionmentioning

confidence: 91%

“…These truncated peptides share a common feature; they correspond to the CIDE-N domain of the CAD protein, a motive implicated in the protein-protein interaction with ICAD [23]. Moreover, it has been reported than the interaction between the CIDE-N domain of CAD and ICAD is increased when a part of the endonuclease domain is also implicated in this interaction [26].…”

Section: 1mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of splice variants of human caspase-activated DNase with CIDE-N structure and function

BAYASCAS

2004

FEBS Letters

View full text Add to dashboard Cite

Internucleosomal DNA fragmentation is an apoptotic event that depends on the activity of different nucleases. Among them, the DNA fragmentation factor B, better known as caspase-activated DNase (CAD), is mainly responsible for this DNA fragmentation in dying cells. CAD is an endonuclease that is chaperoned and inhibited by inhibitor of CAD (ICAD). Activation of CAD needs the cleavage of ICAD by activated caspase-3. During the characterization of the staurosporineinduced apoptotic process in human neuroblastoma cell lines, we have found three novel splice variants of CAD. In all three messengers, the open reading frame is truncated after the second exon of the CAD gene. This truncated open reading frame codifies the CAD protein amino terminal part corresponding to the cell death-inducing DFF45-like effector-N (CIDE-N) domain. We have detected these splicing variants in human tissues and in peripheral white blood cells from 10 unrelated individuals, and their products have been showed to be expressed in certain mouse tissues. We demonstrate that these truncated forms of CAD are soluble proteins that interact with ICAD. We also provided evidences that these CIDE-N forms of CAD promote apoptosis in a caspase-dependent manner.

show abstract

Identification of Regulatory and Catalytic Domains in the Apoptosis Nuclease DFF40/CAD

Abstract: The DNA fragmentation factor (DFF) is composed of two subunits, the 40-kDa caspase-3-activated nuclease (DFF40/CAD) and its 45-kDa inhibitor (DFF45/ICAD).

Cited by 66 publications

References 13 publications

DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells

DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Characterization of splice variants of human caspase-activated DNase with CIDE-N structure and function

Contact Info

Product

Resources

About