The PTP1B mutant PTP1B∆2–4 is a positive regulator of the JAK/STAT signalling pathway in Hodgkin lymphoma
| العنوان: | The PTP1B mutant PTP1B∆2–4 is a positive regulator of the JAK/STAT signalling pathway in Hodgkin lymphoma |
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| المؤلفون: | Malena Zahn, Bianca Kaluszniak, Ralf Marienfeld, Peter Möller |
| المصدر: | Carcinogenesis |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, 0301 basic medicine, Cancer Research, Adolescent, AcademicSubjects/MED00710, Gene mutation, Biology, Biology, Genetics and Epigenetics, stat, Young Adult, 03 medical and health sciences, Exon, 0302 clinical medicine, Cell Line, Tumor, Humans, Phosphorylation, Child, STAT3, Aged, Cell Proliferation, Janus Kinases, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Alternative splicing, JAK-STAT signaling pathway, General Medicine, Middle Aged, Hodgkin Disease, Gene Expression Regulation, Neoplastic, Alternative Splicing, STAT Transcription Factors, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Cancer research, STAT protein, biology.protein, Janus kinase, hormones, hormone substitutes, and hormone antagonists, Signal Transduction |
| الوصف: | The neoplastic Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) depend on chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways to maintain survival and proliferation. Accumulating reports highlight the importance of the inactivation or reduced expression of negative JAK/STAT regulators such as the protein-tyrosine phosphatase 1B (PTP1B/PTPN1) in this process. Various PTPN1 mRNA variants as well as truncated PTP1B proteins were identified in cHL cell lines and primary cHL tumour samples. These PTPN1 mRNA variants lack either one or several exon sequences and therefore render these PTP1B variants catalytically inactive. Here, we show that one of these mutants, PTP1B∆2–4, is not only a catalytically inactive variant, but also augmented the IL-4-induced JAK/STAT activity similar to the recently reported PTP1B∆6 splice variant. Moreover, while PTP1B∆6 diminished the activity and protein levels of PTP1BWT, PTP1BWT remained unaffected by PTP1B∆2–4, arguing for different molecular mechanisms of JAK/STAT modulation by PTP1B∆6 and PTP1B∆2–4. Collectively, these data indicate that PTPN1 variants missing one or more exon sequences originated either from alternative splicing or from gene mutation, create PTP1B gain-of-function variants with oncogenic potential by augmenting JAK/STAT signalling in cHL. We describe the impact of the deletion of exon 2–4 of PTP1B, rendering PTP1B∆2–4 into a positive JAK/STAT regulator similar to PTP1B∆6, highlighting the relevance of exon-deleting alterations to convert a tumour-suppressor into a protein with pro-oncogenic properties. |
| تدمد: | 1460-2180 0143-3334 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::17c03e3b4a8537ed38f9339a6b724c48Test https://doi.org/10.1093/carcin/bgaa144Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....17c03e3b4a8537ed38f9339a6b724c48 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602180 01433334 |
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