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Biomedical subjects

D Knutti

Publications and source records attributed to D Knutti.

7 recordsLinked to original sources
PubMed2001

Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.

Mechanisms and signals that regulate transcriptional coactivators are still largely unknown. Here we provide genetic evidence for a repressor that interacts with and regulates the nuclear receptor coactivator PGC-1. Association with the repressor requires a PGC-1 protein interface that is similar to the one used by nuclear receptors. Removal of the repressor enhances PGC-1 coactivation of steroid hormone responses. We also provide evidence that interaction of the repressor with PGC-1 is regulated by mitogen-activated protein kinase (MAPK) signaling. Activation of the MAPK p38 enhances the activity of wild-type PGC-1 but not of a PGC-1 variant that no longer interacts with the repressor. Finally, p38 activation enhances steroid hormone response in a PGC-1-dependent manner. Our data suggest a model where the repressor and nuclear receptors compete for recruiting PGC-1 to an inactive and active state, respectively. Extracellular signals such as nuclear receptor ligands or activators of the MAPK p38 can shift the equilibrium between the two states.

Amino Acid Motifs↗
PubMed2001

PGC-1, a versatile coactivator.

PGC-1 was originally identified as a transcriptional coactivator of the nuclear receptor PPARgamma. The expression pattern and induction by exposure to cold have implicated PGC-1 in the regulation of energy metabolism and adaptive thermogenesis. Remarkably, PGC-1 overexpression can induce mitochondrial biogenesis and functions. Recent studies show that PGC-1 regulates the activity of several nuclear receptors and other transcription factors, and thus acts in a broader context than previously anticipated. Furthermore, PGC-1 displays the striking ability to interact with components of the splicing machinery. PGC-1 could therefore allow coordinated regulation of transcription and splicing in response to signals relaying metabolic needs. These novel findings are discussed in the context of the proposed physiological functions of PGC-1.

Animals↗
PubMed2000

A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen.

Steroid receptors mediate responses to lipophilic hormones in a tissue- and ligand-specific manner. To identify nonreceptor proteins that confer specificity or regulate steroid signaling, we screened a human cDNA library in a steroid-responsive yeast strain. One of the identified cDNAs, isolated in the screen as ligand effect modulator 6, showed no homology to yeast or Caenorhabditis elegans proteins but high similarity to the recently described mouse coactivator PGC-1 and was accordingly termed hPGC-1. The hPGC-1 DNA encodes a nuclear protein that is expressed in a tissue-specific manner and carries novel motifs for transcriptional regulators. The expression of hPGC-1 in mammalian cells enhanced potently the transcriptional response to several steroids in a receptor-specific manner. hPGC-1-mediated enhancement required the receptor hormone-binding domain and was dependent on agonist ligands. Functional analysis of hPGC-1 revealed two domains that interact with steroid receptors in a hormone-dependent manner, a potent transcriptional activation function, and a putative dimerization domain. Our findings suggest a regulatory function for hPGC-1 as a tissue-specific coactivator for a subset of nuclear receptors.

Animals↗
PubMed1998

Rapid actin-based plasticity in dendritic spines.

Dendritic spines have been proposed as primary sites of synaptic plasticity in the brain. Consistent with this hypothesis, spines contain high concentrations of actin, suggesting that they might be motile. To investigate this possibility, we made video recordings from hippocampal neurons expressing actin tagged with green fluorescent protein (GFP-actin). This reagent incorporates into actin-containing structures and allows the visualization of actin dynamics in living neurons. In mature neurons, recordings of GFP fluorescence revealed large actin-dependent changes in dendritic spine shape, similar to those inferred from previous studies using fixed tissues. Visible changes occurred within seconds, suggesting that anatomical plasticity at synapses can be extremely rapid. As well as providing a molecular basis for structural plasticity, the presence of motile actin in dendritic spines implicates the postsynaptic element as a primary site of this phenomenon.

Actins↗
PubMed1978

[Sonographic diagnosis of gallbladder diseases].

In a prospective study of 174 patients referred for cholecystography, an ultrasound study (gray scale technique) was also carried out and the results of the two examinations were compared. The ultrasound examination served to demonstrate a normal gall bladder in 96% of the patients and, based on typical sonographic findings, permitted the diagnosis of cholecystolithiasis in 97%. The ultrasound examination can be carried out prior to the X-ray study as a screening method and has particular value in the work-up of patients with unclear right upper quadrant abdominal pain.

Adult↗