FKBP12, The 12-kDa FK506-Binding Protein, is a Physiologic Regulator of the Cell Cycle

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 5; pp. 2425 - 2430
• Main Authors: Aghdasi, Bahman, Ye, Keqiang, Resnick, Adam, Huang, Alex, Ha, Hyo Chol, Guo, Xin, Dawson, Ted M., Dawson, Valina L., Snyder, Solomon H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.02.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; Base Sequence; Biological Sciences; Calcium; Cell cycle; Cell Cycle - physiology; Cell cycle proteins; Cell nucleus; Cells; Cells, Cultured; Cellular biology; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cyclins - metabolism; DNA Primers; Fibroblasts; Messenger RNA; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Phosphates; Phosphorylation; Polymerase Chain Reaction; Proteins; Receptors; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Tacrolimus Binding Protein 1A - genetics; Tacrolimus Binding Protein 1A - physiology; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.041614198

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 β (TGF-β) type I receptor. We now demonstrate that cells from FKBP12-deficient (FKBP12-/-) mice manifest cell cycle arrest in G1 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-β1. The p21 up-regulation and cell cycle arrest derive from the overactivity of TGF-β receptor signaling, which is normally inhibited by FKBP12. Cell cycle arrest is prevented by transfection with a dominant-negative TGF-β receptor construct. TGF-β 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-β receptor signaling.