The animal and cell models that uncovered FKBP51 as a regulator of glucocorticoid receptor function.

Many New World primates are glucocorticoid-resistant secondary to expression of low affinity glucocorticoid receptors. We identified the role of FKBP51 in hormone responsiveness by showing that multiple cell lines derived from New World primates share the same activities: (1) soluble cell extracts conferred low binding affinity to high affinity glucocorticoid receptors; (2) FK506 increased receptor binding in soluble cell extracts; and (3) cellular FKBP51 was elevated and FKBP52 was lower. Details of these cell lines and their availability are described.

FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes.

Rationale: Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions.

Objective: Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated.

Methods And Results: Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A).

S100A6 is a positive regulator of PPP5C-FKBP51-dependent regulation of endothelial calcium signaling.

I is a cation current permeating the ISOC channel. In pulmonary endothelial cells, I activation leads to formation of inter-endothelial cell gaps and barrier disruption. The immunophilin FK506-binding protein 51 (FKBP51), in conjunction with the serine/threonine protein phosphatase 5C (PPP5C), inhibits I .

Serine/threonine phosphatase 5 (PP5C/PPP5C) regulates the ISOC channel through a PP5C-FKBP51 axis.

Pulmonary endothelial cells express a store-operated calcium entry current ( I), which contributes to inter-endothelial cell gap formation. I is regulated by a heterocomplex of proteins that includes the immunophilin FKBP51. FKBP51 inhibits I by mechanisms that are not fully understood.

Regulation of store-operated calcium entry by FK506-binding immunophilins.

Calcium entry from the extracellular space into cells is an important signaling mechanism in both physiological and pathophysiological functions. In non-excitable cells, store-operated calcium (SOC) entry represents a principal mode of calcium entry. Activation of SOC entry in pulmonary artery endothelial cells leads to the formation of inter-endothelial cell gaps and subsequent endothelial barrier disruption.

Tissue-specific expression of squirrel monkey chorionic gonadotropin.

Pituitary gonadotropins LH and FSH play central roles in reproductive function. In Old World primates, LH stimulates ovulation in females and testosterone production in males. Recent studies have found that squirrel monkeys and other New World primates lack expression of LH in the pituitary.

Regulation and distribution of squirrel monkey chorionic gonadotropin and secretogranin II in the pituitary.

Secretogranin II (SgII) is a member of the granin family of proteins found in neuroendocrine and endocrine cells. The expression and storage of SgII in the pituitary gland of Old World primates and rodents have been linked with those of luteinizing hormone (LH). However, New World primates including squirrel monkeys do not express LH in the pituitary gland, but rather CG is expressed.

Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth.

We found that the expression levels of N-Myc interactor (Nmi) were low in aggressive breast cancer cell lines when compared with less aggressive cell lines. However, the lower levels in the aggressive lines were inducible by interferon-gamma (IFN-gamma). Because Nmi has been reported to be a transcription cofactor that augments IFN-gamma induced transcription activity, we decided to test whether Nmi regulates expression of Dkk1, which is also inducible by IFN-gamma.

Androgen resistance in squirrel monkeys (Saimiri spp.).

The goal of this study was to understand the basis for high androgen levels in squirrel monkeys (Saimiri spp.). Mass spectrometry was used to analyze serum testosterone, androstenedione, and dihydrotestosterone of male squirrel monkeys during the nonbreeding (n = 7) and breeding (n = 10) seasons.

Increased production of 11beta-hydroxysteroid dehydrogenase type 2 in the kidney microsomes of squirrel monkeys (Saimiri spp.).

In squirrel monkeys (Saimiri spp.), cortisol circulates at levels much higher than those seen in man and other Old World primates, but squirrel monkeys exhibit no physiologic signs of the mineralocorticoid effects of cortisol. These observations suggest that squirrel monkeys have mechanisms for protection of the mineralocorticoid receptor (MR) from these high levels of cortisol.

Molecular cloning of pituitary glycoprotein alpha-subunit and follicle stimulating hormone and chorionic gonadotropin beta-subunits from New World squirrel monkey and owl monkey.

The goal of this study was to characterize the gonadotropins expressed in pituitary glands of the New World squirrel monkey (Saimiri sp.) and owl monkey (Aotus sp.).

Congenital radial and thumb aplasia in a neonatal owl monkey (Aotus nancymaae).

This report describes congenital radial and thumb aplasia in a neonatal owl monkey. Congenital limb deformities in human neonates and Old World primate species have been well characterized. The many probable causes of these congenital defects in skeletal structure include fetal exposure to environmental toxins and genetic influences.

Ultrasonographic monitoring of a spontaneous abortion in an owl monkey (Aotus nancymaae).

This case report describes the ultrasonographic findings during an idiopathic spontaneous abortion in an owl monkey. The female owl monkey presented for a transabdominal ultrasonogram to evaluate her pregnancy. This evaluation is a routine monitoring procedure in our owl monkey breeding colony.

Ovarian stimulation of squirrel monkeys (Saimiri boliviensis boliviensis) using pregnant mare serum gonadotropin.

The application of assisted reproductive technologies (ART) to nonhuman primates has created opportunities for improving reproductive management in breeding colonies, and for creation of new animal models by genetic modification. One impediment to the application of ART in Saimiri spp. has been the lack of an effective gonadotropin preparation for ovarian stimulation.

Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids.

Expression of FKBP51, a large molecular weight immunophilin, is strongly enhanced by glucocorticoids, progestins, and androgens. However, the activity of a 3.4-kb fragment of the FKBP51 gene (FKBP5) promoter was only weakly increased by progestin and we show here that it is unresponsive to glucocorticoids and androgens.

Increased activity of the calcineurin-nuclear factor of activated T cells pathway in squirrel monkey B-Lymphoblasts identified by PowerBlot.

New World primate-derived cell lines were instrumental in identifying the primary factors causing glucocorticoid resistance in these primate species. Their use is expanding because it has been recognized that some of these cell lines exhibit differential sensitivity to retroviral infection. To enhance their utility as cell models, we have further characterized one of these cell lines, squirrel monkey-derived B-lymphoblast (SML) cells, using PowerBlot.

Organization of the human FK506-binding immunophilin FKBP52 protein gene (FKBP4).

FKBP52 is a widely expressed FK506-binding immunophilin that possesses peptidylprolyl isomerase activity and a tetratricopeptide repeat involved in protein-protein interaction. FKBP52 plays an important role in steroid receptor function and is implicated in other diverse processes, including regulation of transcription, cation channel activity, and gene transfer efficiency. Reported here is the genomic organization of the human FKBP52 gene (FKBP4), which shares all but one of the same exon-intron boundaries as the structurally related immunophilin FKBP51 gene (FKBP5).