Journal article
JunD Protects the Liver from Ischemia/Reperfusion Injury by Dampening AP-1 Transcriptional Activation
The Journal of biological chemistry, Vol.283(11), pp.6687-6695
03/14/2008
DOI: 10.1074/jbc.M705606200
PMCID: PMC3593645
PMID: 18182393
Abstract
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.
Details
- Title: Subtitle
- JunD Protects the Liver from Ischemia/Reperfusion Injury by Dampening AP-1 Transcriptional Activation
- Creators
- Jennifer J Marden - Molecular and Cellular Biology Interdisciplinary Graduate Program, University of Iowa College of Medicine, Iowa City, Iowa 52242Yulong Zhang - Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242Fredrick D Oakley - Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242Weihong Zhou - Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242Meihui Luo - Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242Hong Peng Jia - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242Paul B McCray - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242Moshe Yaniv - Institut Pasteur, 75724 Paris Cedex 15, FranceJonathan B Weitzman - Institut Pasteur, 75724 Paris Cedex 15, FranceJohn F Engelhardt - Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.283(11), pp.6687-6695
- DOI
- 10.1074/jbc.M705606200
- PMID
- 18182393
- PMCID
- PMC3593645
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Grant note
- R01 DK051315 || DK / National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
- Language
- English
- Date published
- 03/14/2008
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Microbiology and Immunology; Pulmonary Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025416002771
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