Disease relevance of MADD

• These findings place DENN/MADD and JNK in important hypoxia insult-induced intracellular signaling pathways [1].
• When PA-1 ovarian cancer cells that are devoid of endogenous IG20 variant, but express higher levels of DENN-SV, were transfected with IG20, they showed reduced cell proliferation and increased susceptibility to apoptosis induced by TNFalpha, TRAIL and gamma-radiation [2].
• The Jurkat human leukemia, PLC/PRF/5 human hepatoma, and NS-1 mouse myeloma cell lines as well as the MRC-5 human fetal lung and Vero monkey kidney cell lines were treated successfully with four separate DENN-targeted antisense oligodeoxynucleotides (ODNs) to abrogate DENN expression [3].

High impact information on MADD

• We found reduced DENN/MADD and increased TRADD expression immunohistochemically in the hippocampus in areas of AD pathology compared to normal controls but little intraneuronal colocalization [4].
• The mitogen-activated kinase activating death domain protein (MADD) that is differentially expressed in neoplastic vs. normal cells (DENN) was identified as a substrate for c-Jun N-terminal kinase 3, the first demonstration of such an activity for this stress-activated kinase that is predominantly expressed in the brain [1].
• IG20, a MADD splice variant, increases cell susceptibility to gamma-irradiation and induces soluble mediators that suppress tumor cell growth [5].
• In addition, the conditioned media from HeLa IG20 cells stopped the growth of ovarian PA-1 cancer cells in the G(1)-G(0) cell cycle stage [5].
• Consistent with previous results, overexpression of DENN-SV and IG20 in HeLa cells conferred resistance and susceptibility, respectively, to the effects of gamma-irradiation [5].

Biological context of MADD

• Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor necrosis factor alpha-induced apoptosis and activation of caspase-8 and -3 [6].
• Our results show that IG20 can promote TNF-alpha-induced apoptosis and activation of caspase-8 and -3 and suggest that it may play a novel role in the regulation of the pleiotropic effects of TNF-alpha through alternative splicing [6].
• These data support the anti-apoptotic and cell survival role of DENN, especially in malignant cells, and its interaction with specific genes and proteins involved in the apoptotic and cell cycle pathways [7].
• DENN/MADD regulates the recycling of Rab3 small G proteins under normal conditions and has an essential role in Ca(2+)-dependent neurotransmitter release and exocytosis [8].
• Together, our data show that IG20 gene can play a novel and significant role in regulating cell proliferation, survival and death through alternative mRNA splicing [2].

Anatomical context of MADD

• Functional analyses of these variants in permanently transfected HeLa cells revealed that IG20 and DENN-SV render them more susceptible or resistant to tumor necrosis factor alpha (TNF-alpha)-induced apoptosis, respectively [6].
• We previously reported that messenger RNA expression of DENN (differentially expressed in normal and neoplastic cells) is considerably higher in cancer cell lines than in normal cells [7].
• DENN/MADD is a component of a signalling protein complex that is localized to the cytosol and exerts multiple functions by using different binding partners [8].
• Although NPDC-1 bound Rab3 GEP in vitro, it seems unlikely to be involved in Ca2+-dependent exocytosis and, thus, in synaptic vesicle trafficking [9].
• We then examined whether Rab3 GEP and GAP were involved in Ca2+-dependent exocytosis by use of human growth hormone (GH) co-expression assay system of cultured PC12 cells [10].

Associations of MADD with chemical compounds

• We found that actinomycin D treatment of KS cells selectively abolished expression of mitogen-activated protein kinase-activating death domain protein (MADD), a novel TNFR-I-associated death domain protein [11].
• The serine- and leucine-rich DENN protein possesses a RGD cellular adhesion motif and a leucine-zipper-like motif associated with protein dimerization, and shows partial homology to the receptor binding domain of tumor necrosis factor alpha [12].
• MADD is highly homologous to a Rab3 guanine-nucleotide exchange protein (Rab3-GEP) [13].
• The requirement for MADD was highly specific for TNFalpha-induced activation of MAPK but not the related JNK and p38 kinases [14].

Regulatory relationships of MADD

• However, relative to control cells, only cells expressing IG20 showed enhanced TNF-alpha-induced activation of caspase-8 and -3, whereas cells expressing DENN-SV showed either reduced or no caspase activation [6].
• Others, such as human MADD (MAP (Mitogen-activated protein) kinase activating protein containing death domain) and human ST5 (Suppressor of tumoreginicity 5) gene products are involved in regulation of MAPKs (Mitogen-activated protein kinases) signaling pathways [15].

Other interactions of MADD

• We have used the yeast interaction trap to isolate a protein, MADD, that associates with the death domain of TNFR1 through its own C-terminal death domain [16].
• MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase [16].
• Cells transfected with the DENN-SV cDNA show increased resistance to tumor necrosis factor alpha (TNFalpha), TNF-related apoptosis-inducing ligand (TRAIL), etoposide, and vinblastine treatment, whereas overexpression of IG20 enhanced susceptibility to both intrinsic (drugs) and extrinsic (e.g., TNFalpha and TRAIL) death signals [5].
• DENN displays significant homology to Rab3 GEP, a rat GDP/GTP exchange protein specific for Rab3 small G proteins implicated in intracellular vesicle trafficking [12].
• The protein, named rabconnectin-3, bound both Rab3 GEP and GAP [17].

Analytical, diagnostic and therapeutic context of MADD

• Molecular cloning, structural analysis, and expression of a human IRLB, MYC promoter-binding protein: new DENN domain-containing protein family emerges small star, filled [18].

References