NDLI: FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

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FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

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FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ye, K. Dawson, T. M. Ha, H. C. Aghdasi, B. Resnick, A. Huang, A. Snyder, S. H. Dawson, V. L. Guo, X.
Description	Author Affiliation: Aghdasi B ( Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA..);
Abstract	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.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	5
Volume Number	98
Language	English
Publisher	National Academy of Sciences
Publisher Date	2001-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cell Cycle Physiology Tacrolimus Binding Protein 1A Animals Cells, Cultured Cyclin-Dependent Kinase Inhibitor P21 Cyclins Metabolism DNA Primers Mice Mice, Knockout Mitogen-Activated Protein Kinases Polymerase Chain Reaction Receptors, Transforming Growth Factor Beta Signal Transduction Genetics Up-Regulation P38 Mitogen-Activated Protein Kinases Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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