title: Advances in revealing the molecular targets downstream of oxidative stress-induced proapoptotic kinase signaling in diabetic embryopathy.
abstract: Preexisting maternal diabetes is a high-risk factor of diabetic embryopathy, such as neural tube defects and congenital heart defects. Maternal diabetes significantly increases the production of reactive oxygen species, resulting in oxidative stress and diabetic embryopathy. Multiple cellular and metabolic factors contribute to these processes. Forkhead box O (FoxO)-3a has been demonstrated as a key transcription factor in the signaling transduction pathways responsible for maternal diabetes-induced birth defects. Apoptosis signal-regulating kinase 1 (ASK1) activated by oxidative stress stimulates nuclear translocation of FoxO3a, resulting in the overexpression of tumor necrosis factor receptor 1-associated death domain protein, which, in turn, leads to caspase-8 activation and apoptosis. Maternal diabetes-activated c-Jun N-terminal kinase (JNK)-1/2, downstream effectors of ASK1, can be blocked by superoxide dismutase-1 overexpression, suggesting that oxidative stress is responsible for JNK1/2 signaling activation. Deletion of JNK1/2 significantly suppressed the activity of FoxO3a. These observations indicate that maternal diabetes-induced oxidative stress stimulates the activation of ASK1, JNK1/2, FoxO3a, tumor necrosis factor receptor 1-associated death domain protein, caspase-8 cleavage, and finally, apoptosis and diabetic embryopathy.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: E Albert
authors.initials: EA
authors.lastname: Reece
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD. Electronic address: pyang@fpi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D005260:Female; D005315:Fetal Diseases / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D018384:Oxidative Stress; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047888:Receptors, Tumor Necrosis Factor, Type I; D013482:Superoxide Dismutase; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; D053181:Caspase 8
keywords: apoptosis; birth defects; kinase signaling; maternal diabetes; oxidative stress