Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling

University of Regensburg Medical School, D-93053 Regensburg, Germany.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 05/2007; 34(4):603-11. DOI: 10.1016/j.mcn.2007.01.002
Source: PubMed


The Ski family of nuclear oncoproteins represses transforming growth factor-beta (TGF-beta) signaling through inhibition of transcriptional activity of Smad proteins. In this study, we identified a novel gene, fussel-15 (functional smad suppressing element on chromosome 15) with high homology to the recently discovered Fussel-18 protein. Both, Fussel-15 and Fussel-18, share important structural features, significant homology and similar genomic organization with the homolog Ski family members, Ski and SnoN. Unlike Ski and SnoN, which are ubiquitously expressed in human tissues, Fussel-15 expression, like Fussel-18, is much more restricted in its expression and is principally found in the nervous system of mouse and humans. Interestingly, Fussel-15 expression is even more restricted in adulthood to Purkinje cells of human cerebellum. In contrast to Fussel-18 that interacts with Smad 2, Smad3 and Smad4 and has an inhibitory activity on TGF-beta signaling, Fussel-15 interacts with Smad1, Smad2 and Smad3 molecules and suppresses mainly BMP signaling pathway but has only minor effects on TGF-beta signaling. This new protein expands the family of Ski/Sno proto-oncoproteins and represents a novel molecular regulator of BMP signaling.

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    • "In this study we report the discovery and functional analysis of a novel gene, the Drosophila ortholog of the human functional suppressing element 15 (fussel-15), to which we refer as fussel (fuss). The gene has been identified in an in silico screen as the Drosophila homolog of human fussel-(15) [32], a member of the Ski-Sno family in vertebrates. To study the function of Fuss in BMP/Act-ß signaling, we made use of GAL4 induced mis-expression in the Drosophila wing, an excellent model system to investigate BMP signaling. "
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    ABSTRACT: The TGF-β/BMP signaling cascades control a wide range of developmental and physiological functions in vertebrates and invertebrates. In Drosophila melanogaster, members of this pathway can be divided into a Bone Morphogenic Protein (BMP) and an Activin-ß (Act-ß) branch, where Decapentaplegic (Dpp), a member of the BMP family has been most intensively studied. They differ in ligands, receptors and transmitting proteins, but also share some components, such as the Co-Smad Medea (Med). The essential role of Med is to form a complex with one of the two activating Smads, mothers against decapentaplegic (Mad) or dSmad, and to translocate together to the nucleus where they can function as transcriptional regulators of downstream target genes. This signaling cascade underlies different mechanisms of negative regulation, which can be exerted by inhibitory Smads, such as daughters against decapentaplegic (dad), but also by the Ski-Sno family. In this work we identified and functionally analyzed a new member of the Ski/Sno-family, fussel (fuss), the Drosophila homolog of the human functional suppressing element 15 (fussel-15). fuss codes for two differentially spliced transcripts with a neuronal expression pattern. The proteins are characterized by a Ski-Sno and a SAND homology domain. Overexpression studies and genetic interaction experiments clearly reveal an interaction of fuss with members of the BMP pathway, leading to a strong repression of BMP-signaling. The protein interacts directly with Medea and seems to reprogram the Smad pathway through its influence upon the formation of functional Mad/Medea complexes. This leads amongst others to a repression of downstream target genes of the Dpp pathway, such as optomotor blind (omb). Taken together we could show that fuss exerts a pivotal role as an antagonist of BMP signaling in Drosophila melanogaster.
    PLoS ONE 08/2012; 7(8):e42349. DOI:10.1371/journal.pone.0042349 · 3.23 Impact Factor
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    • "SKOR1 is a transcriptional co-repressor which acts by inhibiting gene expression induced by bone morphogenetic (BMP) family growth factors [13,14]. In humans, SKOR1 is mainly expressed in the adult cerebellum [14], but it may play a more important role as an induced repressor of gene transcription and subsequent cellular differentiation during early central nervous system (CNS) development. Mouse studies have shown this gene to be important for determining cell fate in the developing CNS [14,15]. "
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    ABSTRACT: Recent genome-wide association studies have identified a single nucleotide polymorphism within the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults. MAP2K5 is a component of the MAPK-family intracellular signaling pathways, responding to extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). In this study, we examined the association of this variant in two cohorts of children from Sweden and Greece. We examine the association of rs2241423 to BMI in a cohort of 474 Swedish children admitted for treatment of childhood obesity and 519 children matched for gender, ethnicity and socioeconomic background from the Stockholm area, as well as a cross-sectional cohort of 2308 Greek school children (Healthy Growth Study). Children were genotyped using a predesigned TaqMan polymorphism assay. Logistic regression was used to test for an association of rs2241423 to obesity in the cohort of Swedish children. Linear regression was used to test for an association of rs2241423 to BMI z-score and phenotypic measurements of body adiposity in the cohort of Greek children. Models were adjusted for age and gender. In the cohort of Greek children the model was also adjusted for stage of pubertal development. The minor allele of rs2241423, allele A, was associated with a protective effect against obesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64-0.98)), and with a lower BMI z-score in the cohort of Greek children (p = 0.028, β = -0.092). No association to phenotypic measurements of body fat distribution could be observed in our study. rs2241423 was associated with BMI and obesity in two independent European cohorts suggesting a role for MAP2K5 in early weight regulation.
    BMC Medical Genetics 05/2012; 13(1):36. DOI:10.1186/1471-2350-13-36 · 2.08 Impact Factor
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    • "(G) Immunohistochemical stainings of human colon, mammary gland, uterus and skin sections were negative for MIA. be expressed in Purkinje cells [11] (Figure 1E). As further positive controls, we stained human melanoma sections, which were strongly positive for MIA (Figure 1F). "
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    ABSTRACT: Immunohistochemistry is an important and valuable technique in many fields of research, although several common pitfalls can lead to wrong or misinterpreted results. A recently published study [1] claims that the protein MIA (melanoma inhibitory activity) is expressed in Purkinje cells in the cerebellum. Careful re-analysis resulted in negative results. Due to these results of our group we feel that this analysis could serve as example for the potential problems in immunohistochemistry caused by the combination of an unspecific antibody and the omission of evaluating control tissue samples.
    International journal of clinical and experimental pathology 01/2012; 5(2):137-9. · 1.89 Impact Factor
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