Article

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

Seattle Children's Research Institute.
Physiological Genomics (Impact Factor: 2.81). 10/2012; 44(23). DOI: 10.1152/physiolgenomics.00085.2012
Source: PubMed

ABSTRACT The discovery of causal mechanisms associated with nonsyndromic craniosynostosis has proven to be a difficult task due to the complex nature of the disease. In this study, differential transcriptome correlation analysis was used to identify two molecularly distinct subtypes of nonsyndromic craniosynostosis, termed subtype A and subtype B. In addition to unique correlation structure, subtype A was also associated with high IGF pathway expression, whereas subtype B was associated with high integrin expression. In order to identify a pathologic link between altered gene correlation/expression and the disease state, phosphorylation assays were performed on primary osteoblast cell lines derived from cases within subtype A or subtype B, as well as on primary osteoblast cell lines with novel IGF1R variants previously reported by our lab (5). Elevated IRS1 (pan-tyr) and GSK3β (ser-9) phosphorylation were observed in two novel IGF1R variants with receptor L domain mutations. In subtype A, a hypomineralization phenotype coupled with decreased phosphorylation of IRS1 (ser-312), p38 (thr-180/tyr-182), and p70S6K (thr-412) was observed. In subtype B, decreased phosphorylation of IRS1 (ser-312) as well as increased phosphorylation of Akt (ser-473), GSK3β (ser-9), IGF1R (tyr-1135/tyr-1136), JNK (thr-183/tyr-187), p70S6K (thr-412) and pRPS6 (ser-235/ser-236) was observed, thus implicating the activation of IRS1-mediated Akt signaling in potentiating craniosynostosis in this subtype. Taken together, these results suggest that despite the stimulation of different pathways, activating phosphorylation patterns for IRS1 were consistent in cell lines from both subtypes and the IGF1R variants, thus implicating a key role for IRS1 in the pathogenesis of nonsyndromic craniosynostosis.

0 Followers
 · 
140 Views
 · 
0 Downloads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligand-receptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the bone remodeling unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.
    10/2013; 2:437. DOI:10.1038/bonekey.2013.171
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca2+ levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca2+ accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.
    Molecular Neurobiology 05/2014; DOI:10.1007/s12035-014-8735-4 · 5.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Toxicogenomics can be broadly defined as the study of how the genetic material responds to toxicant exposure. This sub-discipline of toxicology utilizes numerous genomic technologies to relate adverse toxicologic effects with their associated changes in gene expression. The scope of this review will focus on microarray technology and its use in identifying key biomarkers at both the single gene and pathway levels to elucidate toxicologic mechanisms in the liver. Microarrays have been used to study global transcriptomic changes associated with toxicants for years; however, limited emphasis has been placed on what role their reactive metabolites play in this process. Reactive metabolites, which can be generated by normal oxidative metabolism, have the potential to react with endogenous biomolecules, alter their function, and elicit a toxicogenomic response. Quinoneimines are an example of such a species, eliciting toxicity through the generation of oxidative and electrophilic stress. Five compounds with differing toxicity profiles are evaluated herein that are capable of forming quinoneimine intermediates by cytochrome P450 enzymes. They include acetaminophen (APAP), amodiaquine, atorvastatin, carvedilol, and diclofenac. Perspectives on the consistency between the hepatic gene expression profiles of these quinoneimine-forming agents as well as the untapped value of structure-based transcriptome profiling are discussed in this review.
    Drug Metabolism Reviews 10/2014; 47(1). DOI:10.3109/03602532.2014.978081 · 6.29 Impact Factor
Show more