The Son of sevenless (Sos) gene functions in signaling pathways initiated by the sevenless and epidermal growth factor receptor tyrosine kinases. The Sos gene has now been isolated and sequenced. Its product is a 1595-amino acid protein similar to the CDC25 protein in Saccharomyces cerevisiae, a guanine nucleotide exchange factor that activates Ras. These results imply a role for the ras pathway in Drosophila neuronal development.

Perinatal hypoxic-ischemic encephalopathy (HIE) is associated with high neonatal mortality and severe long-term neurologic morbidity. Yet the mechanisms of brain injury in infants with HIE remain largely elusive. The present study determined a novel mechanism of microRNA-210 (miR-210) in silencing endogenous neuroprotection and increasing hypoxicischemic brain injury in neonatal rats. The study further revealed a potential therapeutic effect of miR-210 inhibition using complementary locked nucleic acid oligonucleotides (miR-210-LNA) in 10-day-old neonatal rats in the Rice-Vannucci model. The underlying mechanisms were investigated with intracerebroventricular injection (i.c.v) of miR-210 mimic, miR-210-LNA, glucocorticoid receptor (GR) agonist and antagonist. Luciferase reporter gene assay was conducted for identification of miR-210 targeting GR 3’untranslated region. The results showed that the HI treatment significantly increased miR-210 levels in the brain, and miR-210 mimic significantly decreased GR protein abundance and exacerbated HI brain injury in the pups. MiR-210-LNA administration via i.c.v. 4 hours after the HI insult significantly decreased brain miR-210 levels, increased GR protein abundance, reduced HI-induced neuronal death and brain infarct size, and improved long-term neurological function recovery. Of importance, the intranasal delivery of miR-210-LNA 4 hours after the HI insult produced similar effects in decreasing HI-induced neonatal brain injury and improving neurological function later in life. Altogether, the present study provides evidence of a novel mechanism of miR-210 in a neonatal HI brain injury model, and suggests a potential therapeutic approach of miR-210 inhibition in the treatment of neonatal HIE.

Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize 1) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-beta signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and beta-catenin and TGF-beta pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins alpha-smooth muscle actin (alpha-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-gamma (PPARgamma) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-beta signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPARgamma agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD.

Although mantle cell lymphoma (MCL) frequently harbors inactivated ataxia telangiectasia mutated (ATM) and p53 alleles, little is known about the molecular phenotypes caused by these genetic changes. We identified point mutations and genomic deletions in these genes in a series of cyclin D1-positive MCL cases and correlated genotype with gene expression profiles and overall survival. Mutated and͞or deleted ATM and p53 alleles were found in 56% (40͞72) and 26% (21͞82) of the cases examined, respectively. Although MCL patients with inactive p53 alleles showed a significant reduction in median overall survival, aberrant ATM status did not predict for survival. Nevertheless, specific gene expression signatures indicative of the mutation and genomic deletion status of each gene were identified that were different from wild-type cases. These signatures were comprised of a select group of genes related to apoptosis, stress responses, and cell cycle regulation that are relevant to ATM or p53 function. Importantly, we found the molecular signatures are different between cases with mutations and deletions, because the latter are characterized by loss of genes colocalized in the same chromosome region of ATM or p53. This information on molecular phenotypes may provide new areas of investigation for ATM function or may be exploited by designing specific therapies for MCL cases with p53 aberrations.cancer ͉ cell cycle ͉ genetics ͉ microarray ͉ signature M antle cell lymphoma (MCL) is an aggressive tumor that accounts for Ϸ6% of all non-Hodgkin lymphoma cases in the U.S., with higher rates in North America (1, 2). Although the median survival of MCL patients is only 3 years, some individuals survive Ͼ10 years from the time of diagnosis (2, 3). There is considerable interest in defining the molecular basis for this clinical heterogeneity to develop better prognostic markers and more effective therapies.MCL corresponds to B cells of the mantle zone of the lymphoid follicles that have acquired distinctive alterations in genes related to cell cycle control and apoptosis (4). The hallmark of these genetic alterations is the t(11;14)(q13;q32) translocation that juxtaposes the IGH locus near the CCND1 gene, resulting in the overexpression of cyclin D1 (5). A subset of MCL cases acquire p53 mutations, and these patients have a significantly shortened median survival relative to cases with wild-type p53 (6-8). Interestingly, the ataxia telangiectasia mutated (ATM) gene, whose product regulates some p53-dependent apoptosis pathways, is mutated or deleted in 25-40% of MCL cases (reviewed in refs. 9 and 10). Although preliminary studies suggest that ATM mutation status does not have a significant impact on patient survival (7, 11), they may have lacked the statistical power to identify more subtle effects on survival, such as the effect of functional subsets of mutations.We determined the ATM and p53 genotypes in a large cohort of MCL cases with previous gene expression profiles to further elucidate the relationship between molecular phe...

Hypertension is a syndrome beyond high blood pressure alone. Hypertension is one of the cardiovascular diseases that may cause cardiovascular remodeling and endothelial dysfunction. Angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors are expressed in most organs and tissues and are implicated in hypertension, endothelial dysfunction, and cardiovascular diseases. Genetic and epigenetic manipulations of the renin angiotensin system play a critical role in programming of cardiovascular diseases, and certain variants of AT1R and AT2R are constitutively predisposed to higher cardiovascular risk and hypertension. The structure-function relationship of angiotensin receptors has been reviewed previously. So, in this review we focused on the structure, expression of angiotensin II receptors, their mode of action, role in cardiovascular pathobiology, and how cardiovascular diseases are programmed in utero. In addition, we described genetic variants of angiotensin receptors, and also discussed possible ways of therapeutic intervensions of Ang II stimulation. Collectively, this information may lead us to future new drug design against cardiovascular diseases.