N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions
Abstract The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targete...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Cell Communication and Signaling |
| Online Access: | https://doi.org/10.1186/s12964-025-02183-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849311050737909760 |
|---|---|
| author | Sana Mumtaz Sheikh Julia Staab Martina Bleyer Aleksandar Ivetic Fred Lühder Oliver Wirths Thomas Meyer |
| author_facet | Sana Mumtaz Sheikh Julia Staab Martina Bleyer Aleksandar Ivetic Fred Lühder Oliver Wirths Thomas Meyer |
| author_sort | Sana Mumtaz Sheikh |
| collection | DOAJ |
| description | Abstract The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targeted mutation in mice expressing an N-terminally truncated STAT1 protein (STAT1-ΔN) typically develops splenomegaly in animals older than 6 months due to the formation of splenic non-Hodgkin lymphomas. The expression of the STAT1-ΔN variant resulted in the disruption of normal spleen architecture by malignant CD3- and CD20-negative tumor cells, which stained positively for both tyrosine-phosphorylated STAT1 and STAT3. Immunoblotting of lysates from isolated tumor cells revealed the cytokine-independent hyperphosphorylation of both STAT proteins, whereas the expression level of NF-κB was significantly reduced. Gel-shift assays showed that the DNA-binding activity of STAT1-ΔN was increased compared to the wild-type protein. This elevated level of tyrosine-phosphorylated STAT1-ΔN did not further increase upon stimulation of isolated tumor cells with either interferon-γ (IFNγ), lipopolysaccharide (LPS), or the combination of both. Since the truncation mutant was unable to accumulate in the nucleus upon cytokine stimulation, real-time PCR data from tumor tissue as well as from isolated, IFNγ/LPS-treated lymphoma cells demonstrated significantly reduced STAT1-regulated target gene expression despite its observed hyperphosphorylation. The nuclear import defect of tyrosine-phosphorylated STAT1-ΔN was associated with an elevated tyrosine-phosphorylation level of its antagonistic homolog STAT3, which is a known oncogene. These data demonstrate that the lack of STAT1 nuclear accumulation interferes with the functional balance between the two STAT proteins and, thereby, promotes the formation of phospho-STAT3-expressing CD3-/- CD20-/- non-Hodgkin lymphomas in the spleens of the diseased animals. |
| format | Article |
| id | doaj-art-b17b924a21b9495c97c0d0bfebf4fe60 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-b17b924a21b9495c97c0d0bfebf4fe602025-08-20T03:53:32ZengBMCCell Communication and Signaling1478-811X2025-04-0123111410.1186/s12964-025-02183-2N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functionsSana Mumtaz Sheikh0Julia Staab1Martina Bleyer2Aleksandar Ivetic3Fred Lühder4Oliver Wirths5Thomas Meyer6Department of Psychosomatic Medicine and Psychotherapy, University Medical Center GöttingenDepartment of Psychosomatic Medicine and Psychotherapy, University Medical Center GöttingenGerman Primate Center, Leibniz Institute for Primate ResearchSchool of Cardiovascular and Metabolic Medicine & Sciences, BHF Centre of Research Excellence, King’s College LondonInstitute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center GöttingenDepartment of Psychiatry and Psychotherapy, University Medical Center GöttingenDepartment of Psychosomatic Medicine and Psychotherapy, University Medical Center GöttingenAbstract The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targeted mutation in mice expressing an N-terminally truncated STAT1 protein (STAT1-ΔN) typically develops splenomegaly in animals older than 6 months due to the formation of splenic non-Hodgkin lymphomas. The expression of the STAT1-ΔN variant resulted in the disruption of normal spleen architecture by malignant CD3- and CD20-negative tumor cells, which stained positively for both tyrosine-phosphorylated STAT1 and STAT3. Immunoblotting of lysates from isolated tumor cells revealed the cytokine-independent hyperphosphorylation of both STAT proteins, whereas the expression level of NF-κB was significantly reduced. Gel-shift assays showed that the DNA-binding activity of STAT1-ΔN was increased compared to the wild-type protein. This elevated level of tyrosine-phosphorylated STAT1-ΔN did not further increase upon stimulation of isolated tumor cells with either interferon-γ (IFNγ), lipopolysaccharide (LPS), or the combination of both. Since the truncation mutant was unable to accumulate in the nucleus upon cytokine stimulation, real-time PCR data from tumor tissue as well as from isolated, IFNγ/LPS-treated lymphoma cells demonstrated significantly reduced STAT1-regulated target gene expression despite its observed hyperphosphorylation. The nuclear import defect of tyrosine-phosphorylated STAT1-ΔN was associated with an elevated tyrosine-phosphorylation level of its antagonistic homolog STAT3, which is a known oncogene. These data demonstrate that the lack of STAT1 nuclear accumulation interferes with the functional balance between the two STAT proteins and, thereby, promotes the formation of phospho-STAT3-expressing CD3-/- CD20-/- non-Hodgkin lymphomas in the spleens of the diseased animals.https://doi.org/10.1186/s12964-025-02183-2 |
| spellingShingle | Sana Mumtaz Sheikh Julia Staab Martina Bleyer Aleksandar Ivetic Fred Lühder Oliver Wirths Thomas Meyer N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions Cell Communication and Signaling |
| title | N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions |
| title_full | N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions |
| title_fullStr | N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions |
| title_full_unstemmed | N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions |
| title_short | N-terminal truncation of STAT1 transcription factor causes CD3- and CD20-negative non-Hodgkin lymphoma through upregulation of STAT3-mediated oncogenic functions |
| title_sort | n terminal truncation of stat1 transcription factor causes cd3 and cd20 negative non hodgkin lymphoma through upregulation of stat3 mediated oncogenic functions |
| url | https://doi.org/10.1186/s12964-025-02183-2 |
| work_keys_str_mv | AT sanamumtazsheikh nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions AT juliastaab nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions AT martinableyer nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions AT aleksandarivetic nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions AT fredluhder nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions AT oliverwirths nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions AT thomasmeyer nterminaltruncationofstat1transcriptionfactorcausescd3andcd20negativenonhodgkinlymphomathroughupregulationofstat3mediatedoncogenicfunctions |