Chakilam, Saritha and Gandesiri, Muktheshwar and Rau, Tilman T. and Agaimy, Abbas and Vijayalakshmi, Mahadevan and Ivanovska, Jelena and Wirtz, Ralph M. and Schulze-Luehrmann, Jan and Benderska, Natalya and Wittkopf, Nadine and Chellappan, Ajithavalli and Ruemmele, Petra and Vieth, Michael and Rave-Fraenk, Margret and Christiansen, Hans and Hartmann, Arndt and Neufert, Clemens and Atreya, Raja and Becker, Christoph and Steinberg, Pablo and Schneider-Stock, Regine (2013) Death-Associated Protein Kinase Controls STAT3 Activity in Intestinal Epithelial Cells. AMERICAN JOURNAL OF PATHOLOGY, 182 (3). pp. 1005-1020. ISSN 0002-9440, 1525-2191
Full text not available from this repository. (Request a copy)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 rote in the inflammation-associated transformation process as confirmed in an A0M+DSS colon carcinogenesis mouse model. DAPK as a negative regulator of STAT3 emerges as therapeutic option in the treatment of ulcerative colitis and UCC. (Am J Pathol 2013, 182: 1005-1020; http://dx.doi.org/10.1016/j.ajpath.2012.11.026)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; SIGNAL-TRANSDUCTION; ULCERATIVE-COLITIS; COLORECTAL-CANCER; TNF-ALPHA; INTERLEUKIN-6 SYNTHESIS; COLON-CANCER; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Apr 2020 12:22 |
| Last Modified: | 23 Apr 2020 12:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17071 |
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