A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells
| Autor: | Ralf Marienfeld, Silke Brüderlein, Karola Dorsch, Peter Möller, Malena Zahn, Anna Mießner, S Wegener, Thomas F. E. Barth, Benjamin Renner, Janine Heinrich, Ingo Melzner |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell signaling Immunology Antineoplastic Agents macromolecular substances Biology Biochemistry stat 03 medical and health sciences Interferon-gamma 0302 clinical medicine polycyclic compounds Humans Protein Isoforms RNA Messenger STAT4 Cell Proliferation Janus Kinases Protein Tyrosine Phosphatase Non-Receptor Type 1 Cell Death Suppressor of cytokine signaling 1 JAK-STAT signaling pathway Cell Biology Hematology Molecular biology Hodgkin Disease Up-Regulation STAT Transcription Factors 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis STAT protein Interleukin-4 Signal transduction Janus kinase Signal Transduction |
| Zdroj: | Blood. 129(11) |
| ISSN: | 1528-0020 |
| Popis: | Chronic activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways is a hallmark of a variety of B-cell lymphomas, including classical Hodgkin lymphoma (cHL). Constitutive JAK/STAT signaling is crucial for survival and proliferation of Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of cHL. Although the molecular basis of this constitutive JAK/STAT signaling in cHL has not been completely understood, accumulating reports highlight the role of an inactivation or reduced expression of negative JAK/STAT regulators such as silencer of cell signaling 1 (SOCS1) or protein-tyrosine phosphatase 1B (PTP1B) in this process. Here, we report the expression of truncated PTP1B mRNA variants identified in cHL cell lines and primary cHL tumor samples lacking either 1 or several exon sequences. One of these novel PTP1B variants, a splice variant lacking exon 6 (PTP1BΔ6), was found expressed at low levels in cHL cell lines. However, serum stimulation of cHL augmented the expression of PTP1BΔ6 significantly. Functional characterization of PTP1BΔ6 revealed a positive effect on interferon-γ- and interleukin-4-induced JAK/STAT activity in HEK293 or HEK293-STAT6 cells, and on the basal STAT activity in stably transfected L-428 and U-HO1 cHL cell lines. Furthermore, PTP1BΔ6 expression increased the proliferation of L-428 and U-HO1 cells and reduced cytotoxic effects of the chemotherapeutical agents gemcitabine and etoposide distinctively. Collectively, these data indicate that PTP1BΔ6 is a positive regulator of JAK/STAT signaling in cHL. |
| Databáze: | OpenAIRE |
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