激酶Kinome和糖皮质激素诱导的凋亡

The Kinome and Glucocorticoid-Induced Apoptosis

糖皮质激素(glucocorticoid,GC)信号系统和激酶Kinome之间有着复杂的相互作用,其中,在GC处理后,由Kinome最终决定细胞的命运。当细胞表达足够水平的糖皮质激素受体(glucocorticoid receptor,GR)和Bim,以及有利于GSK3激活的Kinome时,就会继发细胞凋亡。通过防止Bim的上调和/或抑制GSK3的蛋白激酶,可在细胞内产生GC抵抗。通过抑制JNK、Src、PI3K、Akt或mTOR存活通路,可以克服T淋巴系统和B淋巴系统恶性肿瘤中的GC抵抗。最近已证明星状孢子素和雷帕霉素可以对GC诱导细胞凋亡相抵抗的恶性T淋巴细胞和B淋巴细胞加以有效致敏。这在理论上论证了通过改变细胞的Kinome提高GC疗效的可行性。

In this perspective, I discuss the complex interplay between GC signaling and the kinome that ultimately determines the cell fate after GC treatment. Apoptosis ensues when the cell express sufficient levels of GR and Bim together with a kinome favoring GSK3 activation. Protein kinases that prevent Bim up-regulation and/or inhibit GSK3, confer GC-resistance on the cell. GC-resistance may be overcome in T and B lymphoid malignancies by inhibiting the JNK, Src, PI3K, Akt or mTOR survival pathways. Both staurosporine and rapamycin have recently been proved efficient to sensitize resistant T and B malignant cells to GC-induced apoptosis. This is a proof-ofprinciple that it is possible to improve GC therapy by altering the cell＇s kinome.