Disease relevance of DFFB

• Since the putative neuroblastoma tumour suppressor gene in distal 1p36 is predicted to be maternally expressed, the lack of imprinting and absence of somatic mutations in DFFB indicate that it is probably not the neuroblastoma tumour suppressor gene [1].
• Aberrant caspase-activated DNase (CAD) transcripts in human hepatoma cells [2].
• Expression of caspase-activated DNase, DFF40 accountable for characteristic ladder pattern was easily detectable in Jurkat but not renal cancer cells, providing one possible explanation for the lack of oligonucleosomal DNA fragmentation in apoptotic RCC cells [3].
• Attenuated expression of DFFB is a hallmark of oligodendrogliomas with 1p-allelic loss [4].
• Expression of the endonuclease subunit of DNA fragmentation factor (DFF40) and cleavage of its inhibitor, DFF45, were not sufficient to cause internucleosomal DNA fragmentation in osteosarcoma cells during etoposide-induced apoptosis [5].

Psychiatry related information on DFFB

• Information from the lateral radiograph is routinely incorporated by radiologists in their decision-making process, and thus computer analysis of lateral images may potentially add another dimension to current CAD schemes [6].
• PURPOSE: The primary objectives were to 1) examine the dose-response relationship between physical activity and mortality in individuals with CAD, and 2) determine whether the aforementioned relationship is consistent within strata of other personal characteristics [7].
• In vivo imaging biomarkers of risk and successful risk reduction are therefore sought, but the information on possible in vivo imaging biomarkers is less mature than activities in CAD [8].
• Incidence of Stress and Psychosocial Factors on Musculoskeletal Disorders in CAD and Data Entry [9].
• PURPOSE: Despite many smoking cessation programs, many patients with CAD continue to smoke or re-smoke [10].

High impact information on DFFB

• Furthermore, we demonstrate that the CIDE-N of CIDE-B regulates enzymatic activity of the DFF40/ DFF45 complex in vitro [11].
• The extra DNA is usually linked to the short arm of chromosome B9, which retains CAD at its normal site [12].
• We propose that, in the initial event of CAD gene amplification, much of the short arm is transferred from one B9 chromosome to another [12].
• Using this assay, inverted duplications were detected in amplified DNA (both DM and HSR configurations) containing the myc gene (16-50 copies/cell) in four human tumor cell lines and in amplified DNA containing the CAD gene (30-200 copies/cell) in three PALA-resistant BHK cell lines [13].
• The flies deficient in the ICAD gene did not express CAD, and did not undergo apoptotic DNA fragmentation during embryogenesis and oogenesis [14].

Chemical compound and disease context of DFFB

• The gene of caspase-activated DNase (CAD), the key enzyme for nucleosome cleavage during apoptosis, is mapped at chromosome 1p36, a region usually associated with hemizygous deletions in human cancers, particularly in hepatoma (HCC) [2].
• From October 1978 to October 1981, 135 patients with disseminated transitional cell carcinomas of the urinary tract, with either measurable or evaluable disease, were randomized to receive either cis-diamminedichloroplatinum (DDP) or cyclophosphamide (CTX), Adriamycin (ADR) (Adria Laboratories, Columbus, Ohio), and DDP (CAD) [15].
• Assays using recombinant FIH and HIF-alpha fragments revealed that FIH is the enzyme that hydroxylates the CAD asparagine residue, that the activity is directly inhibited by cobalt(II) and limited by hypoxia, and that the oxygen in the alcohol of the hydroxyasparagine residue is directly derived from dioxygen [16].
• The trifunctional carbamoylphosphate synthetase/aspartate transcarbamyltransferase/dihydroorotase (CAD) gene is hormone responsive in MCF-7 and ZR-75 breast cancer cells, and this response is inhibited by the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [17].
• METHODS: The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD [18].

Biological context of DFFB

• We have characterised the DFFB gene, encoding the active subunit of the apoptotic nuclease DNA fragmentation factor (DFF40) [1].
• We have also mapped a processed DFFB pseudogene to chromosome 9 [1].
• DFFB itself has seven coding exons spanning 10 kb [1].
• Here we analyzed the effect of heat shock protein 70 (Hsp70) on CAD activity in T-cell receptor (TCR)-induced apoptosis using a T-cell line (TAg-Jurkat) [19].
• Western blotting was used to measure pro-caspase-9, caspase-3, DFF45, the activated nuclease CPAN and poly (ADP-ribose) polymerase, a DNA repair enzyme inactivated by caspase-3 [20].

Anatomical context of DFFB

• Heat shock protein 70 binds caspase-activated DNase and enhances its activity in TCR-stimulated T cells [19].
• Furthermore, the purified Hsp70 dose-dependently augmented DNA-fragmentation activity of caspase-3-activated CAD in a cell-free system [19].
• Apoptosis induction by T-2 toxin: activation of caspase-9, caspase-3, and DFF-40/CAD through cytosolic release of cytochrome c in HL-60 cells [21].
• Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells [22].
• Caspase-3 cleavage and nuclear localization of caspase-activated DNase in human temporal lobe epilepsy [23].

Associations of DFFB with chemical compounds

• Using DNA-binding assay, we show that curcumin does not disrupt the DNA-DFF40/CAD interaction [22].
• Activation and accumulation of 40-50 kD DFF40-like DNases in nuclei of palmitate-treated apoptotic MCF-7 were detected by SDS-DNA-PAGE assay [24].
• CAD immobilization was mediated by its NH2 terminus independently of its DNA-binding activity and correlated with its association to the interchromosomal space [25].
• Alternatively spliced CAD transcripts with fusion of exon 1 to exon 7 were isolated in most of the examined samples including HCC cells and normal controls [2].
• Merbarone induces activation of caspase-activated DNase and excision of chromosomal DNA loops from the nuclear matrix [26].

Physical interactions of DFFB

• These results suggest that Hsp70 binds free CAD in TCR-stimulated T cells to stabilize and augment its activity [19].
• DNA topoisomerase IIalpha interacts with CAD nuclease and is involved in chromatin condensation during apoptotic execution [27].

Regulatory relationships of DFFB

• Purified DFF40 alone possesses intrinsic nuclease activity that is inhibited by its association with DFF45 [28].
• These results indicate that the the binding of Hsp70 to the activated CAD via the peptide-binding domain augments its activity [19].
• Our study demonstrates that CAD is downregulated at the mRNA and protein level during the erythroid differentiation in TF-1 cells [29].
• Erythropoietin activates caspase-3 and downregulates CAD during erythroid differentiation in TF-1 cells - a protection mechanism against DNA fragmentation [29].
• Conversely, PARP-1 enhanced the DNase activity of DFF40 in the absence of NAD(+) [30].

Other interactions of DFFB

• We show that the CIDE-N of CIDE-B interacts with CIDE-N domains of both DFF40 and DFF45 [11].
• DFFB maps to 1p36, near the imprinted putative tumour suppressor gene TP73 [1].
• Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G [31].
• TP73, DFFB and SHREW1 are the only known genes located in these deletion regions, while the others are uncharacterised novel genes [32].
• The contribution of apoptosis-inducing factor, caspase-activated DNase, and inhibitor of caspase-activated DNase to the nuclear phenotype and DNA degradation during apoptosis [33].

Analytical, diagnostic and therapeutic context of DFFB

• We propose a novel paradigm for the regulation of CAD in the nucleus, involving unrestricted accessibility of chromosomal DNA at the initial phase of apoptosis, followed by its nuclear immobilization that may prevent the release of the active nuclease into the extracellular environment [25].
• Subcellular fractionation determined levels of CAD were significantly higher in the nuclear fraction of TLE samples compared with controls, and semiquantitative immunohistochemistry revealed cleaved caspase-3 positive cells in TLE sections but not controls [23].
• The functional CAD gene was localized to human chromosome 1p36.3 by fluorescent in situ hybridization [34].
• Molecular cloning and characterization of human caspase-activated DNase [34].
• In addition, immunoprecipitation with DFF40 followed by Western blot with active caspase-3 antibody revealed the presence of active caspase-3 in DFF40-immunopositive 20kDa proteins [35].

References