Browsing by Subject "SRC"

Sort by: Order: Results:

Now showing items 1-4 of 4
  • Narva, Elisa; Stubb, Aki; Guzman, Camilo; Blomqvist, Matias; Balboa, Diego; Lerche, Martina; Saari, Markku; Otonkoski, Timo; Ivaska, Johanna (2017)
    Cell-type-specific functions and identity are tightly regulated by interactions between the cell cytoskeleton and the extracellular matrix (ECM). Human pluripotent stem cells (hPSCs) have ultimate differentiation capacity and exceptionally low-strength ECM contact, yet the organization and function of adhesion sites and associated actin cytoskeleton remain poorly defined. We imaged hPSCs at the cell-ECM interface with total internal reflection fluorescence microscopy and discovered that adhesions at the colony edge were exceptionally large and connected by thick ventral stress fibers. The actin fence encircling the colony was found to exert extensive Rho-ROCK-myosin-dependent mechanical stress to enforce colony morphology, compaction, and pluripotency and to define mitotic spindle orientation. Remarkably, differentiation altered adhesion organization and signaling characterized by a switch from ventral to dorsal stress fibers, reduced mechanical stress, and increased integrin activity and cell-ECM adhesion strength. Thus, pluripotency appears to be linked to unique colony organization and adhesion structure.
  • Chmielarz, Piotr; Er, Safak; Konovalova, Julia; Bandres, Laura; Hlushchuk, Irena; Albert, Katrina; Panhelainen, Anne; Luk, Kelvin; Airavaara, Mikko; Domanskyi, Andrii (2020)
    Background Parkinson's disease (PD) is associated with proteostasis disturbances and accumulation of misfolded alpha-synuclein (alpha-syn), a cytosolic protein present in high concentrations at pre-synaptic neuronal terminals. It is a primary constituent of intracellular protein aggregates known as Lewy neurites or Lewy bodies. Progression of Lewy pathology caused by the prion-like self-templating properties of misfolded alpha-syn is a characteristic feature in the brains of PD patients. Glial cell line-derived neurotrophic factor (GDNF) promotes survival of mature dopamine (DA) neurons in vitro and in vivo. However, the data on its effect on Lewy pathology is controversial. Objectives We studied the effects of GDNF on misfolded alpha-syn accumulation in DA neurons. Methods Lewy pathology progression was modeled by the application of alpha-syn preformed fibrils in cultured DA neurons and in the adult mice. Results We discovered that GDNF prevented accumulation of misfolded alpha-syn in DA neurons in culture and in vivo. These effects were abolished by deletion of receptor tyrosine kinase rearranged during transfection (RET) or by inhibitors of corresponding signaling pathway. Expression of constitutively active RET protected DA neurons from fibril-induced alpha-syn accumulation. Conclusions For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded alpha-syn propagation in DA neurons, uncovered underlying receptors, and investigated the involved signaling pathways. These results demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD. (c) 2020 International Parkinson and Movement Disorder Society
  • Parri, Elina; Kuusanmäki, Heikki; van Adrichem, Arjan J.; Kaustio, Meri; Wennerberg, Krister (2020)
    STAT3 mediates signalling downstream of cytokine and growth factor receptors where it acts as a transcription factor for its target genes, including oncogenes and cell survival regulating genes. STAT3 has been found to be persistently activated in many types of cancers, primarily through its tyrosine phosphorylation (Y705). Here, we show that constitutive STAT3 activation protects cells from cytotoxic drug responses of several drug classes. To find novel and potentially targetable STAT3 regulators we performed a kinase and phosphatase siRNA screen with cells expressing either a hyperactive STAT3 mutant or IL6-induced wild type STAT3. The screen identified cell division cycle 7-related protein kinase (CDC7), casein kinase 2, alpha 1 (CSNK2), discoidin domain-containing receptor 2 (DDR2), cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 4-kinase 2-alpha (PI4KII), C-terminal Src kinase (CSK) and receptor-type tyrosine-protein phosphatase H (PTPRH) as potential STAT3 regulators. Using small molecule inhibitors targeting these proteins, we confirmed dose and time dependent inhibition of STAT3-mediated transcription, suggesting that inhibition of these kinases may provide strategies for dampening STAT3 activity in cancers.
  • Palokangas, Silja (Helsingin yliopisto, 2018)
    Objectives. Most athletes seem to recover gradually within the first 10 days after sports-related concussion (SRC), however a minority of athletes have persistent symptoms. To date, the recovery of Finnish athletes has not been researched. The aim of this study was to research the neuropsychological outcome and recovery trajectory after SRC on average a one-month period in Finnish youth ice hockey players. Both cognitive performance (verbal memory, visual memory, visual motor speed, reaction time) and self-reported symptoms were assessed. Individual clinical recovery was also monitored. It was hypothesized that cognitive performance would decrease (in one or more domains) and that the amount of self-reported symptoms would increase during the first few days after SRC. In addition, it was hypothesized that both cognitive performance and self-reported symptoms would return to baseline levels on average within 10 days after SRC. Methods. The sample of the study (N = 24) was collected in the research project “Heads in the Game” (Pää pelissä -projekti). It consisted of youth ice hockey players who got a SRC during game season 2015–2016 and were in a comprehensive follow-up team. All participants were Finnish, male and aged 14–20 (M = 16.75, SD = 1.59). The baseline performance of each player was assessed before game season. Performance after SRC was assessed in maximum four assessment points until players were clinically recovered. Assessment was done by ImPACT-test. Statistical analyses were performed by linear mixed models. Results and conclusions. Cognitive deficits were observed during the first few days after SRC, however deficits were significant only in reaction time. In addition, self-reported symptoms increased during the first few days after SRC, but this increase was not significant. On average cognitive performance and self-reported symptoms returned to at least baseline levels in 8 days (6–19 days) after SRC. These results suggest that particularly reaction time could be sensitive to SRC. The recovery of Finnish youth ice hockey players took place on average in the typical time course observed in previous studies, however there was variability within individuals.