10 research outputs found

    mTOR pathway occupies a central role in the emergence of latent cancer cells

    No full text
    Abstract The current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis

    The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy

    No full text
    Currently, the success of targeted anticancer therapies largely depends on the correct understanding of the dormant state of cancer cells, since it is increasingly regarded to fuel tumor recurrence. The concept of cancer cell dormancy is often considered as an adaptive response of cancer cells to stress, and, therefore, is limited. It is possible that the cancer dormant state is not a privilege of cancer cells but the same reproductive survival strategy as diapause used by embryonic stem cells (ESCs). Recent advances reveal that high autophagy and mTOR pathway reduction are key mechanisms contributing to dormancy and diapause. ESCs, sharing their main features with cancer stem cells, have a delicate balance between the mTOR pathway and autophagy activity permissive for diapause induction. In this review, we discuss the functioning of the mTOR signaling and autophagy in ESCs in detail that allows us to deepen our understanding of the biology of cancer cell dormancy

    G1 checkpoint is compromised in mouse ESCs due to functional uncoupling of p53-p21Waf1 signaling

    No full text
    <div><p></p><p>Mouse embryonic stem cells (mESCs) lack of G1 checkpoint despite that irradiation (IR) activates ATM/ATR-mediated DDR signaling pathway. The IR-induced p53 localizes in the nuclei and up-regulates <i>p21/Waf1</i> transcription but that does not lead to accumulation of p21/Waf1 protein. The negative control of the p21Waf1 expression appears to occur at two levels of regulation. First, both <i>p21/Waf1</i> gene transcription and the p21/Waf1 protein content increase in mESCs treated with histone-deacetylase inhibitors, implying its epigenetic regulation. Second, proteasome inhibitors cause the p21/Waf1 accumulation, indicating that the protein is a subject of proteasome-dependent degradation in ESСs. Then, the dynamics of IR-induced p21Waf1 protein show its accumulation at long-term time points (3 and 5 days) that coincides with an increase in the proportion of G1-phase cells, down-regulation of <i>Oct4</i> and <i>Nanog</i> pluripotent gene transcription and activation of endoderm-specific genes <i>sox17</i> and <i>afp</i>. In addition, nutlin-dependent stabilization of p53 in mESC was also accompanied by the accumulation of p21/Waf1 as well as restoration of G1 checkpoint and an onset of differentiation. Thus, the lack of functional p21/Waf1 is indispensable for maintaining self-renewal and pluripotency of mESCs.</p></div

    De Novo Variant in the <i>KCNJ9</i> Gene as a Possible Cause of Neonatal Seizures

    No full text
    Background: The reduction in next-generation sequencing (NGS) costs allows for using this method for newborn screening for monogenic diseases (MDs). In this report, we describe a clinical case of a newborn participating in the EXAMEN project (ClinicalTrials.gov Identifier: NCT05325749). Methods: The child presented with convulsive syndrome on the third day of life. Generalized convulsive seizures were accompanied by electroencephalographic patterns corresponding to epileptiform activity. Proband WES expanded to trio sequencing was performed. Results: A differential diagnosis was made between symptomatic (dysmetabolic, structural, infectious) neonatal seizures and benign neonatal seizures. There were no data in favor of the dysmetabolic, structural, or infectious nature of seizures. Molecular karyotyping and whole exome sequencing were not informative. Trio WES revealed a de novo variant in the KCNJ9 gene (1:160087612T > C, p.Phe326Ser, NM_004983), for which, according to the OMIM database, no association with the disease has been described to date. Three-dimensional modeling was used to predict the structure of the KCNJ9 protein using the known structure of its homologs. According to the predictions, Phe326Ser change possibly disrupts the hydrophobic contacts with the valine side chain. Destabilization of the neighboring structures may undermine the formation of GIRK2/GIRK3 tetramers necessary for their proper functioning. Conclusions: We believe that the identified variant may be the cause of the disease in this patient but further studies, including the search for other patients with the KCNJ9 variants, are needed
    corecore