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PNAS 98 (5): 2425-2430

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

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

Bahman Aghdasi*, Keqiang Ye*, Adam Resnick*, Alex Huang*, Hyo Chol Ha*, Xin Guo{dagger}, Ted M. Dawson{dagger}, Valina L. Dawson{dagger}, and Solomon H. Snyder*,{ddagger},§,¶

Departments of *Neuroscience, {ddagger}Pharmacology and Molecular Sciences, §Psychiatry, and {dagger}Neurology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Contributed by Solomon H. Snyder

Accepted for publication December 22, 2000.

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 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.

To whom reprint requests should be addressed at: Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. E-mail: ssnyder{at}jhmi.edu.

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