Reevaluation der potenziell onkogenen, Lymphom-assoziierten Missense-Mutation D427H im STAT3-Molekül

by Lena Sophie Behrendsen
Doctoral thesis
Date of Examination:2023-02-21
Date of issue:2023-01-06
Advisor:Prof. Dr. Thomas Meyer
Referee:Prof. Dr. Thomas Meyer
Referee:Prof. Dr. Susanne Lutz
Persistent Address: http://dx.doi.org/10.53846/goediss-9644

 

 

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Abstract

English

The transcription factor STAT3 (signal transducer and activator of transcription 3) promotes cell proliferation, immunomodulation, and maintenance of a stem cell state, such that its constitutive activation in cells carries oncogenic potential. Numerous point mutations in the STAT3 protein have been described, conferring increased oncogenic properties to the molecule and have been associated with various tumors. Among them is the missense mutation D427H localized in the DNA-binding domain of the STAT3 molecule, which was discovered in association with NK/T-cell lymphomas. However, characterization of the STAT3-D427H mutant performed in this study revealed neither significant cytokine exposure-stimulable hyperphosphorylation nor premature inducible nuclear accumulation, but increased DNA-binding ability was observed with no increase in transcriptional activity compared with the WT molecule. The enhanced binding to STAT-specific DNA binding sites was demonstrated autoradiographically by electrophoretic mobility shift assays using a radiolabeled high-affinity GAS sequence. In summary, these observations are in agreement with the E421K mutation located at the homologous position in the STAT1 molecule, which was also not accompanied by any increase but, on the contrary, even by a significant decrease in the transcriptional activity of the hyperphosphorylated mutant. For this reason, it seems unlikely that the D427H mutant in the STAT3 protein has an oncogenic potential beyond that of the wild-type molecule and thus has pathogenetic significance in the etiology of NK/T-cell lymphomas.
Keywords: Lymphoma-associated missense mutation; Signal transducer and activator of transcription 3 (STAT3); Interleukin-6 signaling; DNA binding; Gene expression
 
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