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

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 ␤ (TGF-␤) 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(WAF1͞CIP1) levels, which cannot be further augmented by TGF-␤1. The p21 up-regulation and cell cycle arrest derive from the overactivity of TGF-␤ receptor signaling, which is normally inhibited by FKBP12. Cell cycle arrest is prevented by transfection with a dominant-negative TGF-␤ receptor construct. TGF-␤ receptor signaling to gene expression can be mediated by SMAD, p38, and ERK͞MAP kinase (extracellular signalregulated kinase͞mitogen-activated protein kinase) pathways. SMAD signaling is down-regulated in FKBP12 ؊/؊ cells. Inhibition of ERK͞MAP 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-␤ receptor signaling.

TGF-β1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes

“…However, there is considerable debate regarding the role of FKBP12 in TGF-␤ signaling, since many members of FKBP are found to be expressed ubiquitously. Therefore, it is still unclear which isoform of FKBP is involved in TGF-␤ signaling in T cells (51)(52)(53)(54). In the absence of TGF-␤1 there could be disequilibria of TGF-␤ type I receptorassociated FKBPs, resulting in leaky Ca 2ϩ release channels.…”

Immunophilin-like TWISTED DWARF1 Modulates Auxin Efflux Activities of Arabidopsis P-glycoproteins

“…3) Modulation by TWD1 is gene-specific, as the related Arabidopsis proteins FKBP12 (28,42) and ROF1/FKBP59 (62) have only slight effects on PGP1-mediated IAA transport compared with TWD1 when coexpressed with PGP1 in yeast. Surprisingly, coexpression of TWD1 in yeast versus protoplast and mammalian cells showed opposite effects on PGP1 activity (inhibition in yeast and stimulation in HeLa cells), suggesting that plant-specific components might be absent in the unicellular eukaryote S. cerevisiae.…”

“…6B). Furthermore, Arabidopsis FKBP12, which represents the most basic FKBP, consisting essentially just of the cis,trans-peptidylprolyl isomerase domain, and which functions as a cell cycle regulator (42), reduced PGP1-mediated IAA efflux (measured as increased IAA retention) only slightly compared with TWD1 (Fig. 6C).…”

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

“…Studies in FKBP12 -/-knockout mice have shown that the FKBP12-FK506 complex is also affecting the expression of cell cycle proteins. An increase in expression of p21 in FKBP12 -/-knockout mice led to G1 cell cycle arrest (125). This mechanism may account for the antiproliferative effect observed in VSMCs (122).…”