Sotos Syndrome Is Associated with Deregulation of the MAPK/ERK-Signaling Pathway
نویسندگان
چکیده
Sotos syndrome (SoS) is characterized by tall stature, characteristic craniofacial features and mental retardation. It is caused by haploinsufficiency of the NSD1 gene. In this study, our objective was to identify downstream effectors of NSD1 and to map these effectors in signaling pathways associated with growth. Genome-wide expression studies were performed on dermal fibroblasts from SoS patients with a confirmed NSD1 abnormality. To substantiate those results, phosphorylation, siRNA and transfection experiments were performed. A significant association was demonstrated with the Mitogen-Activated Protein Kinase (MAPK) pathway. Members of the fibroblast growth factor family such as FGF4 and FGF13 contributed strongly to the differential expression in this pathway. In addition, a diminished activity state of the MAPK/ERK pathway was demonstrated in SoS. The Ras Interacting Protein 1 (RASIP1) was identified to exhibit upregulated expression in SoS. It was shown that RASIP1 dose-dependently potentiated bFGF induced expression of the MAPK responsive SBE reporter providing further support for a link between NSD1 and the MAPK/ERK signaling pathway. Additionally, we demonstrated NSD1 expression in the terminally differentiated hypertrophic chondrocytes of normal human epiphyseal growth plates. In short stature syndromes such as hypochondroplasia and Noonan syndrome, the activation level of the FGF-MAPK/ERK-pathway in epiphyseal growth plates is a determining factor for statural growth. In analogy, we propose that deregulation of the MAPK/ERK pathway in SoS results in altered hypertrophic differentiation of NSD1 expressing chondrocytes and may be a determining factor in statural overgrowth and accelerated skeletal maturation in SoS.
منابع مشابه
P-111: EGFR, ERK, MEK Genes Expression Level in Cumulus Cells of PCOS Women Compared with Healthy Women
Background Poly cystic ovarian syndrome (PCOS) is known as a common endocrine disorder in women at reproductive ages and may cause developmental abnormality in oocyte. ERK has found as a regulator protein of Gap junctions (GJ) function and the level of exchanges between two neighbors cells, for example oocyte and surrounding cumulus cells (CCs) in the mammalian ovary. Such exchange is essential...
متن کاملGene Expression Profile Analysis during Mouse Tooth Development
Introduction: Complex molecular pathways involve in development of different tissues such as teeth. Differential gene expression patterns during teeth development generates different tooth types. Teeth development results from interactions between oral epithelium and underlying ectomesenchyme cells with neural crest origin. Teeth development are regulated by different signaling networks. In thi...
متن کاملBIOINFORMATIC STUDY ON EFFECT OF XANTHOHUMOL AS BIOACTIVE COMPOUND OF HOP IN THE INHIBITION OF THE MAPK/ERK PATHWAY IN THYROID CANCER
Background: Xanthohumol is one of the main bioactive compounds extracted from the female flowers of the hops plant (Humulus lupulus L), that has been shown in several studies to have anti-cancer effects.The MAPK/ERK pathway is one of the key pathways in the regulation of gene expression, cell growth and survival. The abnormal activation of this pathway leads to the uncontrolled cell proliferati...
متن کاملAll-trans Retinoic Acid Regulates the Balance of Treg-Th17 Cells through ERK and P38 Signaling Pathway
متن کامل
Inactivation of mitogen-activated protein kinase signaling pathway reduces caspase-14 expression in impaired keratinocytes
Objective(s):Several investigations have revealed that caspase-14 is responsible for the epidermal differentiation and cornification, as well as the regulation of moisturizing effect. However, the precise regulation mechanism is still not clear. This study was aimed to investigate the expression of caspase-14 in filaggrin-deficient normal human epidermal keratinocytes (NHEKs) and to explore the...
متن کامل