JunD protects the liver from ischemia/reperfusion injury by dampening AP-1 transcriptional activation.
The AP-1 transcription factor modulates a wide range of cellular processes, including cellular proliferation, programmed cell death, and survival. JunD is a major component of the AP-1 complex following liver ischemia/reperfusion (I/R) injury; however, its precise function in this setting remains unclear. We investigated the functional significance of JunD in regulating AP-1 transcription following partial lobar I/R injury to the liver, as well as the downstream consequences for hepatocellular remodeling. Our findings demonstrate that JunD plays a protective role, reducing I/R injury to the liver by suppressing acute transcriptional activation of AP-1. In the absence of JunD, c-Jun phosphorylation and AP-1 activation in response to I/R injury were elevated, and this correlated with increased caspase activation, injury, and alterations in hepatocyte proliferation. The expression of dominant negative JNK1 inhibited c-Jun phosphorylation, AP-1 activation, and hepatic injury following I/R in JunD-/- mice but, paradoxically, led to an enhancement of AP-1 activation and liver injury in JunD+/- littermates. Enhanced JunD/JNK1-dependent liver injury correlated with the acute induction of diphenylene iodonium-sensitive NADPH-dependent superoxide production by the liver following I/R. In this context, dominant negative JNK1 expression elevated both Nox2 and Nox4 mRNA levels in the liver in a JunD-dependent manner. These findings suggest that JunD counterbalances JNK1 activation and the downstream redox-dependent hepatic injury that results from I/R, and may do so by regulating NADPH oxidases.
Marden
Jennifer J
JJ
Molecular and Cellular Biology Interdisciplinary Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Zhang
Yulong
Y
Oakley
Fredrick D
FD
Zhou
Weihong
W
Luo
Meihui
M
Jia
Hong Peng
HP
McCray
Paul B
PB
Yaniv
Moshe
M
Weitzman
Jonathan B
JB
Engelhardt
John F
JF
D000818:Animals; D049109:Cell Proliferation; D005799:Genes, Dominant; D016758:Genes, jun; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D008954:Models, Biological; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun; D015427:Reperfusion Injury / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation
D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C528955:junD protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8