Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, BMPRII

Abstract

Wide variation in glucocorticoid (Gc) sensitivity exists between individuals which may influence susceptibility to, and treatment response of, inflammatory diseases. To determine a genetic fingerprint of Gc sensitivity 100 healthy human volunteers were polarized into the 10% most Gc-sensitive and 10% most Gc-resistant following a low dose dexamethasone (0.25 mg) suppression test. Gene expression profiling of primary lymphocytes identified the 98 most significantly Gc regulated genes. These genes were used to build a subnetwork of Gc signaling, with 54 genes mapping as nodes, and 6 non-Gc regulated genes inferred as signaling nodes. Twenty four of the 98 genes showed a difference in Gc response in vitro dependent on the Gc sensitivity of their donor individuals in vivo. A predictive model was built using both partial least squares discriminate analysis and support vector machines that predicted donor glucocorticoid sensitivity with 87% accuracy. Discriminating genes included bone morphogenetic protein receptor, type II (BMPRII). Transfection studies showed that BMPRII modulated Gc action. These studies reveal a broad base of gene expression that predicts Gc sensitivity and determine a Gc signaling network in human primary T lymphocytes. Furthermore, this combined gene profiling, and functional analysis approach has identified BMPRII as a modulator of Gc signaling.

Glucocorticoid receptor overexpression exerts an antisurvival effect on human small cell lung cancer cells

“…It appears that while GR-eYFP expression is more nuclear, BAD expression appears more cytoplasmic as expected. In addition, several genes were confirmed by qPCR to be downregulated by GR including ADAM (metallopeptidase domain 19 meltrin-b) in agreement with our results in primary human T lymphocytes (Donn et al, 2007), cyclin D2 (CCND2), dedicator of cytokinesis 1 (DOCK1), phosphatidylinositol-4-phosphate 5-kinase, type II, alpha (PIP5K2A) (Figure 8b). …”

Differential modulation of glucocorticoid and progesterone receptor transactivation

“…However, the GME appears to be equally active with both endogenous and synthetic reporter genes Szapary et al, 1992;Collier et al, 1996). Furthermore, it is clear from microarray studies that endogenous genes yield a spectrum of responses that resist generalization (Mittelstadt and Ashwell, 2003;Rogatsky et al, 2003;Donn et al, 2007;Kininis et al, 2007). Therefore, the present results establish that various factors can unequally alter the transcription properties of PR vs. GR in a model system that most likely is recapitulated by some endogenous regulated genes.…”

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

“…The resulting increase in pulmonary BMPR2 mRNA may thus restore the required dampening effects of BMPR-II signalling on IL-6 function. The mechanisms through which glucocorticoids interact with BMPR-II are unclear, but a gene expression profiling study of asthmatics receiving glucocorticoids suggests an important interaction between the sensitivity of the glucocorticoid receptor and BMPR-II [56].…”