A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system.
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. A splice isoform was identified that is a variant of MADD. A protein identical to MADD has been reported to be expressed differentially in neoplastic vs. normal cells and is termed "DENN." We demonstrated differential effects on DENN/MADD in a stressed vs. basal environment. Using in situ hybridization, we localized both the substrate and the kinase to large pyramidal neurons in the human hippocampus. It was interesting that, in four of four patients with neuropathologically confirmed acute hypoxic changes, we detected a unique translocation of DENN/MADD to the nucleolus. These changes were apparent only in neurons sensitive to hypoxia. Moreover, in those cells, translocation of the substrate was accompanied by nuclear translocation of JNK3. These findings place DENN/MADD and JNK in important hypoxia insult-induced intracellular signaling pathways. Our conclusions are important for future studies for understanding these stress-activated mechanisms.
Zhang
Y
Y
Department of Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033, USA.
Zhou
L
L
Miller
C A
CA
D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D002466:Cell Nucleolus / Q000378:metabolism; D003001:Cloning, Molecular; D053418:Death Domain Receptor Signaling Adaptor Proteins; D015723:Gene Library; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000096:biosynthesis; D020662:Guanine Nucleotide Exchange Factors; D006388:Hemagglutinins / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D013379:Substrate Specificity; D014162:Transfection
D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D006388:Hemagglutinins; C105852:MADD protein, human; D011506:Proteins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases