Evaluation of the putative lymphoma-associated point mutation D427H in the STAT3 transcription factor.
DNA binding
Gene expression
Interleukin-6 signaling
Lymphoma-associated missense mutation
Signal transducer and activator of transcription 3 (STAT3)
Journal
BMC molecular and cell biology
ISSN: 2661-8850
Titre abrégé: BMC Mol Cell Biol
Pays: England
ID NLM: 101741148
Informations de publication
Date de publication:
25 Jun 2022
25 Jun 2022
Historique:
received:
31
01
2022
accepted:
13
06
2022
entrez:
25
6
2022
pubmed:
26
6
2022
medline:
29
6
2022
Statut:
epublish
Résumé
Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that promotes cell proliferation and immunomodulation in untransformed cells and maintains stemness of transformed cells, facilitating invasion and metastasis. Numerous point mutations in the STAT3 protein have been identified that drive malignancy in various tumor entities. The missense mutation D427H localized in the STAT3 DNA-binding domain has been previously reported in patients with NK/T cell lymphomas. To assess the biological activity of this missense mutation, we compared the STAT3-D427H mutant to wild-type (WT) protein as well as the known hyper-active mutant F174A. Although previously reported as an activating mutation, the STAT3-D427H mutant neither showed elevated cytokine-induced tyrosine phosphorylation nor altered nuclear accumulation, as compared to the WT protein. However, the D427H mutant displayed enhanced binding to STAT-specific DNA-binding sites but a reduced sequence specificity and dissociation rate from DNA, which was demonstrated by electrophoretic mobility shift assays. This observation is consistent with the phenotype of the homologous E421K mutation in the STAT1 protein, which also displayed enhanced binding to DNA but lacked a corresponding increase in transcriptional activity. Based on our data, it is unlikely that the D427H missense mutation in the STAT3 protein possesses an oncogenic potential beyond the WT molecule.
Sections du résumé
BACKGROUND
BACKGROUND
Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that promotes cell proliferation and immunomodulation in untransformed cells and maintains stemness of transformed cells, facilitating invasion and metastasis. Numerous point mutations in the STAT3 protein have been identified that drive malignancy in various tumor entities. The missense mutation D427H localized in the STAT3 DNA-binding domain has been previously reported in patients with NK/T cell lymphomas. To assess the biological activity of this missense mutation, we compared the STAT3-D427H mutant to wild-type (WT) protein as well as the known hyper-active mutant F174A.
RESULTS
RESULTS
Although previously reported as an activating mutation, the STAT3-D427H mutant neither showed elevated cytokine-induced tyrosine phosphorylation nor altered nuclear accumulation, as compared to the WT protein. However, the D427H mutant displayed enhanced binding to STAT-specific DNA-binding sites but a reduced sequence specificity and dissociation rate from DNA, which was demonstrated by electrophoretic mobility shift assays. This observation is consistent with the phenotype of the homologous E421K mutation in the STAT1 protein, which also displayed enhanced binding to DNA but lacked a corresponding increase in transcriptional activity.
CONCLUSIONS
CONCLUSIONS
Based on our data, it is unlikely that the D427H missense mutation in the STAT3 protein possesses an oncogenic potential beyond the WT molecule.
Identifiants
pubmed: 35752777
doi: 10.1186/s12860-022-00422-9
pii: 10.1186/s12860-022-00422-9
pmc: PMC9233852
doi:
Substances chimiques
STAT3 Transcription Factor
0
STAT3 protein, human
0
DNA
9007-49-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : WI3472/10-1
Organisme : Deutsche Forschungsgemeinschaft
ID : ME1648/4-3
Informations de copyright
© 2022. The Author(s).
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