A calcineurin inhibitory protein overexpressed in Down's syndrome interacts with the product of a ubiquitously expressed transcript

Abstract

The Down's syndrome candidate region 1 (DSCR1) protein, encoded by a gene located in the human chromosome 21, interacts with calcineurin and is overexpressed in Down's syndrome patients. As an approach to clarifying a putative function for this protein, in the present study we used the yeast two-hybrid system to identify DSCR1 partners. The two-hybrid system is a method that allows the identification of protein-protein interactions through reconstitution of the activity of the yeast GAL 4 transcriptional activator. The gene DSCR1 fused to the GAL 4 binding domain (BD) was used to screen a human fetal brain cDNA library cloned in fusion with the GAL 4 activation domain (AD). Three positive clones were found and sequence analysis revealed that all the plasmids coded for the ubiquitously expressed transcript (UXT). UXT, which is encoded in human Xp11, is a 157-amino acid protein present in both cytosol and nucleus of the cells. This positive interaction of DSCR1 and UXT was confirmed in vivo by mating the yeast strain AH109 (MATa) expressing AD-UXT with the strain Y187 (MATα) expressing BD-DSCR1, and in vitro by coimmunoprecipitation experiments. These results may help elucidate a new function for DSCR1 and its participation in Down's syndrome pathogenesis.

UXT (Ubiquitously Expressed Transcript) causes mitochondrial aggregation

“…Thus, it remains to be determined whether UXT and C19ORF5 converge at a similar or different point to trigger mitochondrial aggregation. UXT also interacts with DSCR1, human Down's syndrome critical region gene 1 (Silveira et al 2004). The Drosophila melanogaster homolog of DSCR1 is associated with mitochondria, and a regulator of mitochondrial function and integrity, and thus DSCR1 has been proposed to play a role in the mitochondrial dysfunction observed in Down's syndrome (Chang and Min 2005).…”

“…Subsequently, UXT, renamed as ART-27, was reported to interact with the androgen receptor, and a role in male sex determination, prostate development and malignant growth was proposed (Markus et al 2002). UXT was also found to interact with a calcineurin-bound Down's syndrome candidate region 1 (DSCR1) protein that is overexpressed in Down's syndrome patients (Silveira et al 2004), and centrosomeassociated protein phosphatase Cdc14A (Zhao et al 2005).…”

Trisomy 21 and Down syndrome: a short review

“…RCAN1 is highly expressed in the human brain and heart suggesting that its overexpression may be involved in the pathogenesis of Down syndrome, particularly mental retardation and/or cardiac defects (Fuentes et al, 1995). Previous studies identified conserved residues involved in the subcellular location of RCAN1 (Pfister et al, 2002) and provided evidence that it may play a functional role in the nucleus, probably as a regulator of transcription (Silveira et al, 2004). Recently, Arron et al (2006) reported that the genes RCAN1 and DYRK1A, both contained within the DSCR, act synergistically to prevent the nuclear occupancy of NFATc transcription factors.…”

Calcineurin activity in children with Mental handicap

“…The DSCR1 gene product is an inhibitor of CaN and its signaling pathways. In Down's syndrome patients, DSCR1 is highly expressed in neurons within the cerebral cortex, hippocampus, substantia niagra, thalamus and medulla oblongata and interacts physically and functionally with CaN A, the catalytic subunit of the Ca 2+ /CaM dependent protein phosphatase PP2B thus leading to the above condition (4,5,6). A disturbance of calcium homeostasis is believed to play an important role in the neurodegeneration of the brain of Alzheimers's disease (AD) patients.…”

“…Prenatal condition includes genetic (chromosomal or single gene disorders), environmental (infections, drugs, toxemia, maternal diseases, fetal growth retardation, etc) and multifactorial (recognized sequestration, cytokinesis, sporulation and mating (3). Calcineurin has also been implicated in certain diseases such as neuronal neoplasms, Down's syndrome, Alzheimers disease (AD), brain ischemia and cardiac hypertrophy (4,5,6). Induction of long term depression of the hippocampal neurons, modulation of the activities of the sodium channels, L-type calcium channels, NMDA receptors and heat stable inhibitors of protein phosphotase I, calcium mediated apoptosis, redistribution of integrins and regulation of intracellular calcium channels are few other cellular events influenced by calcineurin.…”