IL-6 up-regulates mcl-1 in human myeloma cells through JAK / STAT rather than ras / MAP kinase pathway.
Mcl-1 is an anti-apoptotic member of the Bcl-2 family which is tightly regulated during myeloid and B cell differentiation. We have recently reported that Mcl-1 is expressed in human myeloma cells and that Mcl-1 and Bcl-x(L) expression are correlated. In the current study, we demonstrate that IL-6, a survival factor for the human myeloma cell line MDN, rapidly up-regulates Mcl-1 whereas it has no effect on Bcl-2 protein level. In MDN cells, IL-6 induces both extracellular signal-regulated protein kinase (ERK)1,2 and STAT3 activation whereas STAT1 and STAT5 activation remains undetectable. Furthermore, while investigating the IL-6 signaling pathway leading to Mcl-1 up-regulation, we show that a janus kinase (JAK)-2 inhibitor is able to inhibit both STAT3 activation and Mcl-1 up-regulation whereas an MAP/ERK kinase (MEK) inhibitor has no effect. In conclusion, our data suggest the involvement of the JAK / STAT pathway but not of the Ras / mitogen-activated protein (MAP) kinase pathway in IL-6-induced Mcl-1 up-regulation.
Puthier
D
D
Inserm U463, Institut de biologie, Nantes, France.
Bataille
R
R
Amiot
M
M
D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System / Q000276:immunology; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000276:immunology
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2