Protective effect of Homer 1a on tumor necrosis factor-α with cycloheximide-induced apoptosis is mediated by mitogen-activated protein kinase pathways.
Although Homer 1, of the postsynaptic density, regulates apoptosis, the signaling mechanisms are not fully elucidated. In this study, we found that tumor necrosis factor-α (TNF-α)/cycloheximide (CHX) treatment transiently increased Homer 1a (the short variant of Homer 1), but did not affect Homer 1b/c (the long variant of Homer 1). Overexpression of Homer 1a blocked TNF-α/CHX-induced apoptotic cell death, whereas inhibition of Homer 1a induction enhanced the pro-apoptotic effect of TNF-α/CHX treatment. Moreover, brain-derived neurotrophic factor, as a potential activator of endogenous Homer 1a, inhibited apoptotic cell death after TNF-α/CHX treatment through induction of Homer 1a. Since three major mitogen-activated protein kinase (MAPK) pathways have important roles in apoptosis, we examined if Homer 1a is involved in the effects of MAPK pathways on apoptosis. It was shown that inhibition of the ERK1/2 pathway increased the expression and the protective effect of Homer 1a, but inhibition of the p38 pathway produced the opposite effect. Cross-talk among MAPK pathways was also associated with the regulation of Homer 1a during apoptotic cell death. Blocking the p38 pathway increased the activity in the ERK1/2 pathway, while inhibition of ERK1/2 pathway abolished the effect of p38 inhibitor on Homer 1a. Furthermore, Homer 1a reversely affected the activation of MAPK pathways. These findings suggest that Homer 1a plays an important role in the prevention of apoptotic cell death and contributes to distinct regulatory effects of MAPK pathways on apoptotic cell death.
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 15 Changle Xi Road, Xian, 710032, PR China. xiaoqu@fmmu.edu.cn
Peng
P
Luo
Yongbo
Y
Zhao
Dong
D
Li
Tao
T
Chen
Sanzhong
S
Li
Xiaodong
X
Chao
Wenbo
W
Liu
Lei
L
Zhang
Yan
Y
Qu
Xiaofan
X
Jiang
Gang
G
Lu
Waisang
W
Poon
Zhou
Z
Fei
D000310:Adrenal Gland Neoplasms; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D057809:HEK293 Cells; D000072233:Homer Scaffolding Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016716:PC12 Cells; D010673:Pheochromocytoma; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000873:Anthracenes; D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D005419:Flavonoids; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D003513:Cycloheximide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one