Aghdasi B, Ye K, Resnick A, Huang A, Ha H C, Guo X, Dawson T M, Dawson V L, Snyder S H
Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA..
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2425-30. doi: 10.1073/pnas.041614198. Epub 2001 Feb 20.
FKBP12, the 12-kDa FK506-binding protein, is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506, binds tightly to intracellular calcium release channels and to the transforming growth factor beta (TGF-beta) type I receptor. We now demonstrate that cells from FKBP12-deficient (FKBP12(-/-)) mice manifest cell cycle arrest in G(1) phase and that these cells can be rescued by FKBP12 transfection. This arrest is mediated by marked augmentation of p21(WAF1/CIP1) levels, which cannot be further augmented by TGF-beta1. The p21 up-regulation and cell cycle arrest derive from the overactivity of TGF-beta receptor signaling, which is normally inhibited by FKBP12. Cell cycle arrest is prevented by transfection with a dominant-negative TGF-beta receptor construct. TGF-beta receptor signaling to gene expression can be mediated by SMAD, p38, and ERK/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathways. SMAD signaling is down-regulated in FKBP12(-/-) cells. Inhibition of ERK/MAP kinase fails to affect p21 up-regulation. By contrast, activated phosphorylated p38 is markedly augmented in FKBP12(-/-) cells and the p21 up-regulation is prevented by an inhibitor of p38. Thus, FKBP12 is a physiologic regulator of cell cycle acting by normally down-regulating TGF-beta receptor signaling.
FKBP12是一种12千道尔顿的FK506结合蛋白，是一种普遍存在的丰富蛋白质，它作为免疫抑制剂药物FK506的受体，与细胞内钙释放通道和转化生长因子β（TGF-β）I型受体紧密结合。我们现在证明，来自FKBP12缺陷（FKBP12(-/-)）小鼠的细胞在G(1)期表现出细胞周期停滞，并且这些细胞可以通过FKBP12转染得到挽救。这种停滞是由p21(WAF1/CIP1)水平的显著升高介导的，而TGF-β1不能进一步升高其水平。p21的上调和细胞周期停滞源于TGF-β受体信号传导的过度活跃，而该信号传导通常受到FKBP12的抑制。用显性负性TGF-β受体构建体转染可防止细胞周期停滞。TGF-β受体向基因表达的信号传导可由SMAD、p38和ERK/MAP激酶（细胞外信号调节激酶/丝裂原活化蛋白激酶）途径介导。SMAD信号传导在FKBP12(-/-)细胞中下调。抑制ERK/MAP激酶未能影响p21的上调。相比之下，活化的磷酸化p38在FKBP12(-/-)细胞中显著增加，并且p21的上调可被p38抑制剂阻止。因此，FKBP12是一种细胞周期的生理调节因子，其作用是通过正常下调TGF-β受体信号传导来实现的。
