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Titolo:
FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle
Autore:
Aghdasi, B; Ye, KQ; Resnick, A; Huang, A; Ha, HC; Guo, X; Dawson, TM; Dawson, VL; Snyder, SH;
Indirizzi:
Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 urosci, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205USA Johns Hopkins Univ Baltimore MD USA 21205 Mol Sci, Baltimore, MD 21205USA Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 ychiat, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 Neurol, Baltimore, MD 21205 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 5, volume: 98, anno: 2001,
pagine: 2425 - 2430
SICI:
0027-8424(20010227)98:5<2425:FT1FPI>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
GROWTH-FACTOR-BETA; RYANODINE RECEPTOR FUNCTION; P-GLYCOPROTEIN FUNCTION; CYCLOSPORINE-A; I RECEPTORS; KINASE; INHIBITOR; CALCINEURIN; FAMILY; CYCLOPHILIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Snyder, SH Johns Hopkins Univ, Sch Med, Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA Johns Hopkins Univ 725 N Wolfe St Baltimore MD USA 21205 05 USA
Citazione:
B. Aghdasi et al., "FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle", P NAS US, 98(5), 2001, pp. 2425-2430

Abstract

FKBP12, the 12-kDa FK506-binding protein, is a ubiquitous abundant proteinthat acts as a receptor for the immunosuppressant drug FK506, binds tightly to intracellular calcium release channels and to the transforming growth factor beta (TCF-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 befurther 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 ofERK/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.

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Documento generato il 06/07/20 alle ore 08:11:16