An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden

Abstract

Regulation of age-related changes in gene expression underlies many diseases. We previously discovered the first puberty-onset gene switch, the age-related stability element (ASE)/age-related increase element (AIE)-mediated genetic mechanism for agerelated gene regulation. Here, we report that this mechanism underlies the mysterious puberty-onset amelioration of abnormal bleeding seen in hemophilia B Leyden. Transgenic mice robustly mimicking the Leyden phenotype were constructed. Analysis of these animals indicated that ASE plays a central role in the puberty-onset amelioration of the disease. Human factor IX expression in these animals was reproducibly nullified by hypophysectomy, but nearly fully restored by administration of growth hormone, being consistent with the observed sex-independent recovery of factor IX expression. Ets1 was identified as the specific liver nuclear protein binding only to the functional ASE, G/CAG-GAAG, and not to other Ets consensus elements. This study demonstrates the clinical relevance of the first discovered pubertyonset gene switch, the ASE/AIE-mediated regulatory mechanism.factor IX ͉ growth hormone ͉ sex hormone ͉ puberty ͉ gene switch

Development of a bioassay to screen for chemicals mimicking the anti-aging effects of calorie restriction

“…Interestingly, DFCR-RE2 contains two sequences similar to this ASE, namely GAGGCAG, in its middle region. Mutational studies demonstrated that this sequence (GAGGCAG) does not bind to any proteins present in nuclear extracts, including Ets1 [25]. Further studies are needed to determine whether there is a functional relationship between the ASE and DFCR-RE2.…”

“…Kurachi et al [24,25] identified an age-related stability element (ASE) that regulates age-related gene expression. They found an ASE, (C/G)AGGAAG, containing an Ets transcription factor consensus motif (GGAA), that was bound specifically by Ets1.…”

Protein Phosphatase 2A (PP2A) Regulates Low Density Lipoprotein Uptake through Regulating Sterol Response Element-binding Protein-2 (SREBP-2) DNA Binding

“…8A, Con Ppp2ca, lane 7). This type of result, where the addition of antibody does not result in a supershift, still indicates specific binding and has been previously observed (36,37). Binding was specific because no binding was observed to a mutated SRE in the presence of antibody (Fig.…”

Some Recent Results on Models of Dynamical Electroweak Symmetry Breaking

“…In this talk we will review some of our recent results in this area [4]- [14] obtained in collaboration with T. Appelquist, M. Piai, N. Christensen, and M. Kurachi. (The work with Kurachi is also discussed in his talk [15]. )…”

“…In particular, Refs. [28] and [13] have used solutions of Schwinger-Dyson and Bethe-Salpeter equations to evaluate S [15].…”