1,721,217 research outputs found
Nuclear protein kinase isoforms and apoptosis
No full textThe process of apoptosis is regulated at multiple levels through phosphorylation by several different protein kinases. The protein kinase C (PKC) family of isozymes have been shown to exert both inhibitory and stimulatory influences on apoptosis. During the apoptotic process phosphorylative events are known to occur also at the nuclear level. Evidence suggests that PKC isoforms play a key role in some steps that lead to nuclear disassembly during the execution phase of apoptosis. This review highlights the recent progress made in determining the roles played by individual PKC nuclear isoforms in the control of apoptosis
Selective distribution of multiple protein kinase C isoforms in mouse cerebellar cortex.
No full textAn immunohistochemical study concerning the distribution of protein kinase C isoforms, a lipid-regulated serine/threonine kinase essential for signal transduction, was performed in mice cerebellar cortex, with particular emphasis on the localization of -iota and -lambda isozymes. By the means of immunoblotting analyses we detected the presence of 11 PKC subspecies in whole cerebellar extracts. Immunoreactivity on cryostat sections revealed, using polyclonal and monoclonal antibodies, that a few isoforms were widely but discretely distributed in all three cortical layers (molecular, granular and Purkinje cells) whereas other isozymes were present in a limited neuronal compartment. Overall, the distribution of several isoforms was in agreement with data obtained by other authors using rat cerebellum. As far as -iota and -lambda isozymes were concerned, we found them abundantly expressed in endothelial cells. Moreover, protein kinase C-lambda was also present in the body of Purkinje cell, conceivably associated with a 200-kDa neurofilament component. In all, these results hint at the possibility that in the cerebellar cortex at least some protein kinase C isoforms are involved in functions other than signal transduction at the synaptic level
Advances in understanding the mechanisms of evasive and innate resistance to mTOR inhibition in cancer cells
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Atypical isoenzymes of PKC-iota, -lambda, -mu: relative distribution in mouse foetal and neonatal organs.
No full textNuclear localization and signalling activity of inositol lipids
No full textIt has been recently shown that also the nucleus is a site for both synthesis and hydrolysis of the phosphorylated forms of phosphatidylinositol. Among the enzymes of the cycle we and others have demonstrated that phospholipase C specific for inositol lipids (PLC) is one of the main steps of the inositol lipid cycle. The PLC family and namely the type raised a noticeable interest since, because of their common COOH-terminus, it has been shown a nuclear localisation in addition to that at the plasma membrane. The autonomous intranuclear inositide cycle is endowed, besides the PLC, with conventional lipid kinases and phosphatidylinositol 3 kinase (PI 3-kinase) which plays an important role in granulocytic differentiation. The combination of morphology and molecular biology gave us the opportunity to localise the sites inside the nucleus where the cycle takes place and to understand the physiological significance of such a subcellular compartmentalisation both during cell growth and differentiation
An immunohistochemical study of protein kinase C distribution in fetal mouse vertebral column.
No full textUsing polyclonal antibodies we have studied the distribution of protein kinase C in fetal mouse low thoracic vertebrae. By means of a pan protein kinase C antiserum recognizing the catalytic domain of the enzyme, we show that protein kinase C is markedly expressed in chondrocytes before birth. The enzyme seems to be very abundant in the more mature cells that are close to ossification centres as well as the periphery of the intervertebral disc, although it can also be detected in chondrocytes. In order to establish which protein kinase C isoenzyme(s) the chondrocytes produce, we employed polyclonal isoenzyme-specific antisera developed against three calcium-dependent isoforms (alpha, beta, gamma) and three calcium-independent isoforms (delta, epsilon, zeta). Secondary antibody conjugated to alkaline phosphatase revealed that chondrocytes markedly express the beta-isoform. Cells were also weakly stained by the anti-epsilon serum. The immunostaining was completely abolished by pre-incubating primary antibodies with the peptide antigens to which they were raised. These results suggest that protein kinase C (and particularly the beta isoform) could play an important role in mouse fetal chondrogenesis of the vertebral column
Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer
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The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells
Lipid signaling and cell responses at the nuclear level
No full textThe nucleus is known to be a site for an active lipid metabolism. Although phospholipids are present in the nuclear envelope, evidence suggests that they are also located further inside the nucleus. The function of these intranuclear lipids has escaped clarification for many years. Early experiments showed that they can interact with DNA double helix affecting its thermal stability and can influence RNA synthesis in isolated nuclei. However, in the last 10 years several investigations have suggested that they may be involved in signal transduction pathways at the nuclear level and a growing body of evidence supports this hypothesis
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