Dataset Information

P53 downregulates Down syndrome-associated DYRK1A through miR-1246.

ABSTRACT: Several microRNAs mediate the functions of p53 family members. Here we characterize miR-1246 as a new target of this family. In response to DNA damage, p53 induces the expression of miR-1246 which, in turn, reduces the level of DYRK1A, a Down syndrome-associated protein kinase. Knockdown of p53 has the opposite effect. Overexpression of miR-1246 reduces DYRK1A levels and leads to the nuclear retention of NFATc1, a protein substrate of DYRK1A, and the induction of apoptosis, whereas a miR-1246-specific inhibitor prevented the nuclear import of NFATc1. Together, these results indicate that p53 inhibits DYRK1A expression through the induction of miR-1246.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3147276 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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p53 downregulates Down syndrome-associated DYRK1A through miR-1246.

Zhang Yu Y Liao Jun-Ming JM Zeng Shelya X SX Lu Hua H

EMBO reports 20110603 8

Several microRNAs mediate the functions of p53 family members. Here we characterize miR-1246 as a new target of this family. In response to DNA damage, p53 induces the expression of miR-1246 which, in turn, reduces the level of DYRK1A, a Down syndrome-associated protein kinase. Knockdown of p53 has the opposite effect. Overexpression of miR-1246 reduces DYRK1A levels and leads to the nuclear retention of NFATc1, a protein substrate of DYRK1A, and the induction of apoptosis, whereas a miR-1246-sp ...[more]

PMID: 21637297

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Project description:Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue-specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue-specific-sensitive periods when Dyrk1a regulates cellular processes that shape the long-term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

Dataset Information

P53 downregulates Down syndrome-associated DYRK1A through miR-1246.

Publications

p53 downregulates Down syndrome-associated DYRK1A through miR-1246.

Similar Datasets

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