Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling.
ABSTRACT 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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- "(G) Immunohistochemical stainings of human colon, mammary gland, uterus and skin sections were negative for MIA. be expressed in Purkinje cells  (Figure 1E). As further positive controls, we stained human melanoma sections, which were strongly positive for MIA (Figure 1F). "
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  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. · 1.78 Impact Factor
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ABSTRACT: Le Syndrome d’Impatiences Musculaires de l’Éveil (SIME) est une maladie neurologique caractérisée par un besoin urgent de bouger les jambes. C’est également l’une des causes les plus fréquentes d’insomnie. C’est une maladie très répandue, avec une prévalence de presque 15 % dans la population générale. Les maladies multifactorielles comme le SIME sont souvent le résultat de l’évolution d’une composante génétique et d’une composante environnementale. Dans le cadre du SIME, les études d’association génomique ont permis l’identification de 4 variants à effet modéré ou faible. Cependant, ces quatre variants n’expliquent qu’une faible partie de la composante génétique de la maladie, ce qui confirme que plusieurs nouveaux variants sont encore à identifier. Le rôle des déséquilibres génomiques (Copy Number Variations ou CNVs) dans le mécanisme génétique du SIME est à ce jour inconnu. Cependant, les CNVs se sont récemment positionnés comme une source d’intérêt majeur de variation génétique potentiellement responsable des phénotypes. En collaboration avec une équipe de Munich, nous avons réalisé deux études CNVs à échelle génomique (biopuces à SNP et hybridation génomique comparée (CGH)) sur des patients SIME d’ascendance germanique. À l’aide d’une étude cas-contrôle, nous avons pu identifier des régions avec une occurrence de CNVs différentes pour les patients SIME, comparés à différents groupes contrôles. L’une de ces régions est particulièrement intéressante, car elle est concordante à la fois avec des précédentes études familiales ainsi qu’avec les récentes études d’associations génomiques. Restless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.
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ABSTRACT: Ski and SnoN are two highly related transcription factors that are transcribed from two separate genes named SKI and SKIL, respectively. They are both co-repressors of the Smad-mediated transforming growth factor beta (TGFβ) signaling pathway. Originally they were classified as oncogenes as they have the ability to transform quail fibroblasts. However, they have also been found to have anti-proliferative properties so they are also considered tumor suppressors. They are involved in normal growth and development and thought to be essential as there is evidence that a homozygous mouse knockout of either SKI or SKIL is embryonic lethal. Both Ski and SnoN have been found to be overexpressed in some cancers. This overexpression has been found to be prognostic in some cases. Another prognostic factor in certain cancers is the cytoplasmic localization of these normally nuclear proteins. Other than with the TGFβ signaling pathway, Ski and SnoN are known to have interactions with retinoic acid receptor signaling and the retinoblastoma protein. In order to obtain a better understanding of Ski and SnoN we have studied several aspects of the proteins. First, we identified the nuclear localization signal (NLS) of Ski and proved that this sequence was both necessary and sufficient for nuclear localization. Next, we looked into the correlation of Ski subcellular location and serine phosphorylation status. Here we found that serine phosphorylated Ski is found predominately in the cytoplasm. Finally, we looked at possible involvement of Ski and SnoN in the pediatric cancer rhabdomyosarcoma (RMS). We found there was expression of both of these proteins in cell lines derived from the cancer and in tumor tissue samples. We also found that Ski protein levels in RMS tumor tissue are negatively correlated with RMS tumor group. The data from the Ski phosphorylation studies suggest that this modification may work with the NLS to regulate the subcellular location of Ski. Misregulation of this process may be responsible for the cytoplasmic localization of Ski that we found in RMS. Biomedical Sciences Doctoral University of New Mexico. Biomedical Sciences Graduate Program Bear, David Larson, Richard Winter, Stuart Hartley, Rebecca