Death-associated protein kinase controls STAT3 activity in intestinal epithelial cells.

Abstract

The TNF-IL-6-STAT3 pathway plays a crucial role in promoting ulcerative colitis-associated carcinoma (UCC). To date, the negative regulation of STAT3 is poorly understood. Interestingly, intestinal epithelial cells of UCC in comparison to ulcerative colitis show high expression levels of anti-inflammatory death-associated protein kinase (DAPK) and low levels of pSTAT3. Accordingly, epithelial DAPK expression was enhanced in STAT3(IEC-KO) mice. To unravel a possible regulatory mechanism, we used an in vitro TNF-treated intestinal epithelial cell model. We identified a new function of DAPK in suppressing TNF-induced STAT3 activation as DAPK siRNA knockdown and treatment with a DAPK inhibitor potentiated STAT3 activation, IL-6 mRNA expression, and secretion. DAPK attenuated STAT3 activity directly by physical interaction shown in three-dimensional structural modeling. This model suggests that DAPK-induced conformational changes in the STAT3 dimer masked its nuclear localization signal. Alternatively, pharmacological inactivation of STAT3 led to an increase in DAPK mRNA and protein levels. Chromatin immunoprecipitation showed that STAT3 restricted DAPK expression by promoter binding, thereby reinforcing its own activation by inducing IL-6. This novel negative regulation principle might balance TNF-induced inflammation and seems to play an important role in the inflammation-associated transformation process as confirmed in an AOM+DSS colon carcinogenesis mouse model. DAPK as a negative regulator of STAT3 emerges as therapeutic option in the treatment of ulcerative colitis and UCC.

• Authors: Saritha Chakilam, Muktheshwar Gandesiri, Tilman T Rau, Abbas Agaimy, Mahadevan Vijayalakshmi, Jelena Ivanovska, Ralph M Wirtz, Jan Schulze-Luehrmann, Natalya Benderska, Nadine Wittkopf, Ajithavalli Chellappan, Petra Ruemmele, Michael Vieth, Margret Rave-Fränk, Hans Christiansen, Arndt Hartmann, Clemens Neufert, Raja Atreya, Christoph Becker, Pablo Steinberg, Regine Schneider-Stock
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 3 Pg. 1005-20 (Mar 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23438478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Interleukin-6
• Mutant Proteins
• STAT3 Transcription Factor
• Tumor Necrosis Factor-alpha
• Death-Associated Protein Kinases
• Calcium-Calmodulin-Dependent Protein Kinases

Topics

• Animals
• Apoptosis Regulatory Proteins (chemistry, genetics, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinases (chemistry, genetics, metabolism)
• Cell Nucleus (drug effects, metabolism)
• Cell Transformation, Neoplastic (drug effects, pathology)
• Colitis, Ulcerative (enzymology, pathology)
• Colonic Neoplasms (enzymology, pathology)
• Death-Associated Protein Kinases
• Enzyme Activation (drug effects)
• Epithelial Cells (drug effects, enzymology, pathology)
• Humans
• Hydrogen Bonding (drug effects)
• Hydrophobic and Hydrophilic Interactions (drug effects)
• Inflammation (pathology)
• Interleukin-6 (metabolism)
• Intestinal Mucosa (drug effects, enzymology, pathology)
• Intestines (pathology)
• Mice
• Mice, Inbred C57BL
• Mutant Proteins (metabolism)
• Phosphorylation (drug effects)
• Promoter Regions, Genetic (genetics)
• Protein Binding (drug effects)
• Protein Multimerization (drug effects)
• STAT3 Transcription Factor (chemistry, metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)