Abstract
Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor β-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)α pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-α treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBα signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBα pathway exhibited increased ROS production and TNF-α- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.
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Abbreviations
- AP-1:
-
activating protein-1
- Col:
-
collagen
- ChIP:
-
chromatin immunoprecipitation
- DAPI:
-
4’,6-diamidino-2-phenylindole
- DCF:
-
dichlorodihydrofluorescein (CM-H2DCFDA)
- EMSA:
-
electrophoretic mobility shift assay
- FADD:
-
Fas associated death domain
- FLIP:
-
FADD-like IL-1β-converting enzyme)-inhibitory protein
- GSK:
-
glycogen synthase kinase
- H&E:
-
hematoxylin and eosin staining
- IκBα:
-
nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha
- IKKβ:
-
inhibitor of nuclear factor kappa B kinase beta
- JNK:
-
c-Jun N-terminal kinase
- KCTRL:
-
keratinocyte control
- KTAK1:
-
keratinocyte with TAK1 knockdown
- NAC:
-
N-acetylcysteine
- OTC:
-
organotypic skin co-culture
- PCNA:
-
proliferating cell nuclear antigen
- PDGF:
-
platelet derived growth factor
- PI3K:
-
phosphoinositide-3 kinase
- PKBα:
-
protein kinase B α
- ROS:
-
reactive oxygen species
- SCF:
-
stem cell factor
- siRNA:
-
small interfering ribonucleic acid
- TAK1:
-
transforming growth factor β-activated kinase 1
- TGF-β:
-
transforming growth factor-β
- TNF-α:
-
tumor necrosis factor-α
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
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Acknowledgements
This work was supported by grants from Ministry of Education, Singapore (ARC 8/06) and Nanyang Technological University, Singapore (RGD 127/05, 158/06).
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Lam, C., Tan, M., Tan, S. et al. TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis. Cell Death Differ 18, 1120–1129 (2011). https://doi.org/10.1038/cdd.2010.182
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DOI: https://doi.org/10.1038/cdd.2010.182
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