In vertebrates, smooth muscle cells (SMCs) can reversibly switch between contractile and proliferative phenotypes. This involves various molecular mechanisms to reactivate developmental signaling pathways and induce cell dedifferentiation. The protein RBPMS2 regulates early development and plasticity of digestive SMCs by inhibiting the bone morphogenetic protein pathway through its interaction with NOGGIN mRNA. RBPMS2 contains only one RNA recognition motif (RRM) while this motif is often repeated in tandem or associated with other functional domains in RRM-containing proteins. Herein, we show using an extensive combination of structure/function analyses that RBPMS2 homodimerizes through a particular sequence motif (D-x-K-x-R-E-L-Y-L-L-F: residues 39–51) located in its RRM domain. We also show that this specific motif is conserved among its homologs and paralogs in vertebrates and in its insect and worm orthologs (CPO and MEC-8, respectively) suggesting a conserved molecular mechanism of action. Inhibition of the dimerization process through targeting a conserved leucine inside of this motif abolishes the capacity of RBPMS2 to interact with the translational elongation eEF2 protein, to upregulate NOGGIN mRNA in vivo and to drive SMC dedifferentiation. Our study demonstrates that RBPMS2 possesses an RRM domain harboring both RNA-binding and protein-binding properties and that the newly identified RRM-homodimerization motif is crucial for the function of RBPMS2 at the cell and tissue levels.

PurposeThe aim of this study was to investigate the impact of exercise-induced hypoxaemia (EIH) developed at sea-level on exercise responses at moderate acute altitude.MethodsTwenty three subjects divided in three groups of individuals: highly trained with EIH (n = 7); highly trained without EIH (n = 8) and untrained participants (n = 8) performed two maximal incremental tests at sea-level and at 2,150 m. Haemoglobin O2 saturation (SpO2), heart rate, oxygen uptake (VO2) and several ventilatory parameters were measured continuously during the tests.ResultsEIH athletes had a drop in SpO2 from 99 ± 0.8% to 91 ± 1.2% from rest to maximal exercise at sea-level, while the other groups did not exhibit a similar decrease. EIH athletes had a greater decrease in VO2max at altitude compared to non-EIH and untrained groups (-22 ± 7.9%, -16 ± 5.3% and -13 ± 9.4%, respectively). At altitude, non-EIH athletes had a similar drop in SpO2 as EIH athletes (13 ± 0.8%) but greater than untrained participants (6 ± 1.0%). EIH athletes showed greater decrease in maximal heart rate than non-EIH athletes at altitude (8 ± 3.3 bpm and 5 ± 2.9 bpm, respectively).ConclusionEIH athletes demonstrated specific cardiorespiratory response to exercise at moderate altitude compared to non-EIH athletes with a higher decrease in VO2max certainly due to the lower ventilator and HRmax responses. Thus EIH phenomenon developed at sea-level negatively impact performance and cardiorespiratory responses at acute moderate altitude despite no potentiated O2 desaturation.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are often associated with KIT or PDGFRA gene mutations. GIST cells might arise from the interstitial cells of Cajal (ICCs) or from a mesenchymal precursor that is common to ICCs and smooth muscle cells (SMCs). Here, we analyzed the mRNA and protein expression of RNA-Binding Protein with Multiple Splicing-2 (RBPMS2), an early marker of gastrointestinal SMC precursors, in human GISTs (n=23) by in situ hybridization, quantitative RT-PCR analysis and immunohistochemistry. The mean RBPMS2 mRNA level in GISTs was 42-fold higher than in control gastrointestinal samples (p<0.001). RBPMS2 expression was not correlated with KIT and PDGFRA expression levels, but was higher in GISTs harboring KIT mutations than in tumors with wild type KIT and PDGFRA or in GISTs with PDGFRA mutations that were characterized by the lowest RBPMS2 levels. Moreover, RBPMS2 levels were 64-fold higher in GIST samples with high risk of aggressive behavior than in adult control gastrointestinal samples and 6.2-fold higher in high risk than in low risk GIST specimens. RBPMS2 protein level was high in 87% of the studied GISTs independently of their histological classification. Finally, by inhibiting the KIT signaling pathway in GIST882 cells, we show that RBPMS2 expression is independent of KIT activation. In conclusion, RBPMS2 is up-regulated in GISTs compared to normal adult gastrointestinal tissues, indicating that RBPMS2 might represent a new diagnostic marker for GISTs and a potential target for cancer therapy.