Glycogen synthase kinase 3β (GSK3β) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3β activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3β by phosphorylation at the N terminus, preventing Akt-mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3β substrate β-catenin. Here, we show that p38 mitogen-activated protein kinase (MAPK) also inactivates GSK3β by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of β-catenin. p38 MAPK-mediated phosphorylation of GSK3β occurs primarily in the brain and thymocytes. Activation of β-catenin-mediated signaling through GSK3β inhibition provides a potential mechanism for p38 MAPK-mediated survival in specific tissues.The p38 mitogen-activated protein kinase (MAPK) is activated through phosphorylation primarily by MAPK kinase 3 (MKK3) and MKK6 in response to cellular stress and cytokines. The p38 MAPK pathway functions in the control of differentiation, the blockade of proliferation, and in the induction of apoptosis (1). It is also activated in response to DNA double-stranded breaks (DSBs) induced by ionizing irradiation or chemotherapeutic drugs, and it participates in the induction of a G 2 /M cell-cycle checkpoint (2,3). p38 MAPK can also promote survival (4-6) by unknown mechanisms. During T cell receptor β (TCRβ) rearrangement, V(D)J recombination-mediated DSBs also activate p38 MAPK in immature thymocytes at the double negative 3 (DN3) stage of development (7,8). The expression of a constitutively active mutant of MKK6 [MKK6(Glu)] in thymocytes of transgenic mice (MKK6 transgenic mice) activates a p53-mediated G 2 /M phase cell-cycle checkpoint (8). Like recombination-activating gene (Rag) deficiency, persistent activation of p38 MAPK interferes with the differentiation of thymocytes beyond the DN3 stage. However, MKK6 transgenic thymocytes (but not Rag -/-thymocytes) survive and accumulate in vivo (8), suggesting that
Gene expression regulation is essential for correct functioning of the cell. Complex processes such as development, apoptosis, cell differentiation, and cell cycling require a fine tuning of gene expression. MicroRNAs (miRNAs) are small RNAs that have been recognized as key components of the gene expression regulatory machinery. By sequence complementarity, miRNAs recognize target mRNAs and inhibit their function through degradation or by repressing their translation. The development of the central nervous system (CNS) requires precise and exquisitely regulated gene expression patterns. It is now widely recognized that miRNAs have the capacity to provide such fine regulation both in time and in space. High-throughput analyses as well as classical molecular biology approaches have allowed the identification of essential miRNAs for CNS development and function. Moreover, recent studies in several model organisms are beginning to show intricate regulatory networks involving miRNAs, transcription factors, and epigenetic regulators during CNS development. Here we review recent findings on the role that miRNAs play in the development of the CNS as well as in neuropathologies such as schizophrenia, Parkinson disease, and Alzheimer's disease, among others.
Development of the central nervous system (CNS) requires a precisely coordinated series of events. During embryonic development, different intra- and extracellular signals stimulate neural stem cells to become neural progenitors, which eventually irreversibly exit from the cell cycle to begin the first stage of neurogenesis. However, before this event occurs, the self-renewal and proliferative capacities of neural stem cells and neural progenitors must be tightly regulated. Accordingly, the participation of various evolutionary conserved microRNAs is key in distinct central nervous system (CNS) developmental processes of many organisms including human, mouse, chicken, frog, and zebrafish. microRNAs specifically recognize and regulate the expression of target mRNAs by sequence complementarity within the mRNAs 3′ untranslated region and importantly, a single microRNA can have several target mRNAs to regulate a process; likewise, a unique mRNA can be targeted by more than one microRNA. Thus, by regulating different target genes, microRNAs let-7, microRNA-124, and microRNA-9 have been shown to promote the differentiation of neural stem cells and neural progenitors into specific neural cell types while microRNA-134, microRNA-25 and microRNA-137 have been characterized as microRNAs that induce the proliferation of neural stem cells and neural progenitors. Here we review the mechanisms of action of these two sets of microRNAs and their functional implications during the transition from neural stem cells and neural progenitors to fully differentiated neurons. The genetic and epigenetic mechanisms that regulate the expression of these microRNAs as well as the role of the recently described natural RNA circles which act as natural microRNA sponges regulating post-transcriptional microRNA expression and function during the early stages of neurogenesis is also discussed.
The c-Jun aminoterminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase signaling pathways have been associated with cell death, differentiation and proliferation. CD4+ and CD8+ T cells have different effector functions after antigen stimulation and control specific aspects of the immune response. The studies carried out in our group indicate that the role of JNK and p38 MAP kinases in CD4+ T cells is different from their role in CD8+ T cells. Moreover, these two pathways are not redundant in either T cell population. We have also shown that p38 MAP kinase regulates early stages of T cell development in the thymus. It is therefore important to consider the specific function of these kinases in each T cell population when pharmacological inhibitors of JNK and p38 MAP kinases are used for therapeutic purposes to control the immune response.
Blockade of Kv1.3 K ϩ channels in T cells is a promising therapeutic approach for the treatment of autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus. Vm24 (␣-KTx 23.1) is a novel 36-residue Kv1.3-specific peptide isolated from the venom of the scorpion Vaejovis mexicanus smithi. Vm24 inhibits Kv1.3 channels of human lymphocytes with high affinity (K d ϭ 2.9 pM) and exhibits Ͼ1500-fold selectivity over other ion channels assayed. It inhibits the proliferation and Ca 2ϩ signaling of human T cells in vitro and reduces delayed-type hypersensitivity reactions in rats in vivo. Our results indicate that Vm24 has exceptional pharmacological properties that make it an excellent candidate for treatment of certain autoimmune diseases.
Learning and memory are basic functions of the brain that allowed human evolution. It is well accepted that during learning and memory formation the dynamic establishment of new active synaptic connections is crucial. Persistent synaptic activation leads to molecular events that include increased release of neurotransmitters, increased expression of receptors on the postsynaptic neuron, thus creating a positive feedback that results in the activation of distinct signaling pathways that temporally and permanently alter specific patterns of gene expression. However, the epigenetic changes that allow the establishment of long term genetic programs that control learning and memory are not completely understood. Even less is known regarding the signaling events triggered by synaptic activity that regulate these epigenetic marks. Here we review the current understanding of the molecular mechanisms controlling activity-dependent gene transcription leading synaptic plasticity and memory formation. We describe how Ca(2+) entry through N-methyl-d-aspartate-type glutamate neurotransmitter receptors result in the activation of specific signaling pathways leading to changes in gene expression, giving special emphasis to the recent data pointing out different epigenetic mechanisms (histone acetylation, methylation and phosphorylation as well as DNA methylation and hydroxymethylation) underlying learning and memory.
CD43, the most abundant membrane protein of T lymphocytes, is able to initiate signal transduction pathways that lead to Ca 2؉ mobilization and interleukin-2 production, yet the molecular events involved in CD43's signal transduction pathway are poorly understood. In the present report we show that activation of both purified T lymphocytes and Jurkat cells, through CD43 cross-linking with the anti-CD43 L10 monoclonal antibody, induced CD43 association to Fyn kinase. This association is mediated by the Src homology 3 (SH3) domain of Fyn, since a glutathione S-transferase-Fyn SH3 fusion protein was able to precipitate CD43 from lysates of CD43-activated T cells. A synthetic peptide containing the SH3 binding sites of p85, located within the amino acid sequence 300 ERQPAPALPPKPPKP 314 , was able to inhibit binding of CD43 to Fyn as well as to the glutathione S-transferase-Fyn SH3 fusion protein. We also provide evidence that upon CD43 cross-linking, Fyn is tyrosine-phosphorylated in a time-dependent manner. Our results suggest that CD43 cross-linking on the T cell surface induces the interaction between CD43 and Fyn, presumably through the Fyn SH3 domain and a putative SH3 binding site in CD43, leading to Fyn tyrosine phosphorylation and signal propagation.T cell antigen receptor (TcR) 1 engagement through antigen peptide bound to molecules encoded by the major histocompatibility complex induces the activation of multiple biochemical pathways that result in changes in gene expression, cytokine production, and ultimately T cell proliferation. However, cumulative evidence suggests that additional T cell molecules are essential for optimal T cell activation and function (Hahn et al., 1992). These so called "accessory molecules" have dual functions; they may regulate the adhesive interactions between T cells and antigen-presenting cells, and they may participate in generating activation signals that will synergize with those signals initiated by the TcR. The CD43 molecule (sialophorin, leukosialin, or gp115) is the predominant cell surface sialoglycoprotein expressed on B and T lymphocytes, monocytes, neutrophils, and platelets (Axelsson et al., 1985;Borche et al., 1987;Remold-O'Donnell et al., 1987). CD43 is an integral membrane glycoprotein with a cytoplasmic domain of 123 amino acids. Resting T lymphocytes express a CD43 isoform of 113-122 kDa that contains O-linked tetrasaccharides attached to serine and threonine residues. Upon activation, T lymphocytes express a 125-135-kDa form of CD43 carrying mainly O-linked hexasaccharides (Piller et al., 1988;Piller et al., 1991). The use of monoclonal antibodies (mAbs) for each CD43 isoform (Tomlinson et al., 1994;Shiota et al., 1994) suggest that specific isoforms may have specific functions in T cells. The cytoplasmic domain of CD43 from human, rat, and mouse shows high sequence homology (more than 70% identity), indicating that this protein is involved in regulating T cell function.Earlier observations of defective CD43 expression by T lymphocytes from patients with the ...
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