Constitutive activation of Jak2/STAT5-signalling pathway in MedB-1 cells due to deficient SOCS-1
Bucur, Alexandra Juliana
LicenseStandard (Fassung vom 03.05.2003)
Mediastinal (thymic) B-cell lymphoma (MBL) is a locally highly aggressive tumor and a distinct subclass of diffuse large B-cell lymphoma. MBL exhibits several characteristic genetic abnormalities; including frequent gains of chromosome 9p and distinct high-level amplifications, with the consensus region 9p24, including the Janus Kinase 2 (Jak2) locus. Janus Kinases (Jaks) and their downstream targets, Signal Transducers and Activators of Transcription (STAT proteins) trigger via activation the cytokine induced signal. In MedB-1, a cell line established from a mediastinal B-cell lymphoma, was found about the double dose of Jak2 DNA compared to autologuos fibroblasts, Jak2 m-RNA expression in MedB-1 cells was also higher than in resting peripheral B cells. The results indicated that Jak2 was not overexpressed at the protein level but highly phosphorylated in MedB-1 cells, its protein turn-over being delayed. STAT5 proteins, downstream partner of Jak2 were highly expressed and phosphorylated at the protein level. MedB-1 also expressed high level of Cyclin D1 one of STAT5 target genes important in cell-cycle regulation. SOCS-1(suppressor of cytokine signaling-1) it is one of the most intensively studied Jak2 negative regulators. The central finding in MedB-1 cells is a biallelic mutation in the SOCS-1 gene, which abrogates SOCS box function of the protein. Ectopic expression of wild-type (wt) SOCS-1 in MedB-1 leads to growth arrest and dramatic reduction of phospho-Jak2 and its downstream partner. Ultimately, the target gene cyclin D1 is repressed in transfectants while Rb1, which is silenced in MedB-1, is induced. In conclusion, in MedB-1, the action of phospho-Jak2 is sustained due to defective SOCS-1.