Growth in ataxia telangiectasia

BACKGROUND: Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this disease. At this time, two main severity groups are defined in A-T: classic (the more severe form) and mild. Poor growth is a common problem in classic A-T. An objective of this study was to develop growth references for classic A-T. Another objective was to compare growth patterns in classic A-T and mild A-T with each other and with the general population, using the CDC growth references. A final objective was to examine the effects of chronic infection on height. RESULTS: We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts. Height faltering was more pronounced in females. Birthweight was lower in the classic A-T group compared to mild A-T and the general population, whereas birth length was not. Finally, we investigated height and BMI faltering in relation to number of infections and found no association. CONCLUSIONS: Classic A-T appears to affect growth in utero. Although children appear to grow well in very early life, faltering begins early, and is unrelenting

DYRK1A Autophosphorylation on Serine Residue 520 Modulates Its Kinase Activity via 14-3-3 Binding

Dual-specificity tyrosine-phosphorylated and regulated kinase (DYRK) proteins are an evolutionarily conserved family of protein kinases, with members identified from yeast to humans, that participate in a variety of cellular processes. DYRKs are serine/threonine protein kinases that are activated by autophosphorylation on a tyrosine residue in the activation loop. The family member DYRK1A has been shown to phosphorylate several cytosolic proteins and a number of splicing and transcription factors, including members of the nuclear factor of activated T cells family. In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. We also show that phosphorylation of this residue, which we show is subjected to dynamic changes in vivo, mediates the interaction of DYRK1A with 14-3-3β. A second 14-3-3 binding site is present within the N-terminal of the protein. In the context of the DYRK1A molecule, neither site can act independently of the other. Bacterially produced DYRK1A and the mutant DYRK1A/S520A have similar kinase activities, suggesting that Ser-520 phosphorylation does not affect the intrinsic kinase activity on its own. Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3β, which in turn stimulates the catalytic activity of DYRK1A. These findings provide evidence for a novel mechanism for the regulation of DYRK1A kinase activity

In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma

SummaryKinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G2 checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G2 arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma