Puthier D, Bataille R, Amiot M
Inserm U463, Institut de biologie, Nantes, France.
Eur J Immunol. 1999 Dec;29(12):3945-50. doi: 10.1002/(SICI)1521-4141(199912)29:12<3945::AID-IMMU3945>3.0.CO;2-O.
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.
Mcl-1是Bcl-2家族的一个抗凋亡成员，在髓系和B细胞分化过程中受到严格调控。我们最近报道，Mcl-1在人骨髓瘤细胞中表达，且Mcl-1和Bcl-x(L)的表达相关。在本研究中，我们证明，白细胞介素-6（IL-6）作为人骨髓瘤细胞系MDN的生存因子，可迅速上调Mcl-1，而对Bcl-2蛋白水平无影响。在MDN细胞中，IL-6可诱导细胞外信号调节蛋白激酶（ERK）1、2和信号转导子与转录激活子3（STAT3）激活，而未检测到信号转导子与转录激活子1（STAT1）和信号转导子与转录激活子5（STAT5）激活。此外，在研究导致Mcl-1上调的IL-6信号通路时，我们发现一种janus激酶（JAK）-2抑制剂能够抑制STAT3激活和Mcl-1上调，而丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK）抑制剂则无此作用。总之，我们的数据表明，JAK/STAT通路而非Ras/丝裂原活化蛋白（MAP）激酶通路参与了IL-6诱导的Mcl-1上调。
