ABSTRACT
In humans, the diaphragm adapts to severe chronic obstructive pulmonary disease with (a) fast-to-slow transformations of the fiber types and myofibrillar proteins and (b) increases in the activity of mitochondrial oxidative enzymes. We suggest that progressive endurance training over several decades accounts for these adaptations.
Subject(s)
Diaphragm/physiology , Lung Diseases, Obstructive/physiopathology , Muscle Fatigue/physiology , Adaptation, Physiological , Adenosine Triphosphate/metabolism , Exercise/physiology , Humans , Immunohistochemistry , Myosin Heavy Chains/physiologyABSTRACT
We demonstrate that dexamethasone-mediated transcription activation of the cytochrome P-450c27 promoter involves a physical interaction and functional synergy between glucocorticoid receptor (GR) and Ets2 factor. Ets2 protein binding to a "weak" Ets-like site of the promoter is dependent on GR bound to the adjacent cryptic glucocorticoid response element. Coimmunoprecipitation and chemical cross-linking experiments show physical interaction between GR and Ets2 proteins. Mutational analyses show synergistic effects of Ets2 and GR in dexamethasone-mediated activation of the cytochrome P-450c27 promoter. The DNA-binding domain of GR, lacking the transcription activation and ligand-binding domains, was fully active in synergistic activation of the promoter with intact Ets2. The DNA-binding domain of Ets2 lacking the transcription activation domain showed a dominant negative effect on the transcription activity. Finally, a fusion protein consisting of the GR DNA-binding domain and the transcription activation domain of Ets2 fully supported the transcription activity, suggesting a novel synergy between the two proteins, which does not require the transactivation domain of GR. Our results also provide new insights on the role of putative weak consensus Ets sites in transcription activation, possibly through synergistic interaction with other gene-specific transcription activators.