The Akt (PKB) protein kinases are critical regulators of human physiology that control an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation ...and metabolism. The Akt kinase family is comprised of three highly homologous isoforms: Akt1 (PKBα), Akt2 (PKBβ) and Akt3 (PKBγ). Phenotypic analyses of Akt isoform knockout mice documented Akt isoform specific functions in the regulation of cellular growth, glucose homeostasis and neuronal development. Those studies establish that the functions of the different Akt kinases are not completely overlapping and that isoform-specific signaling contributes to the diversity of Akt activities. However, despite these important advances, a thorough understanding about the specific roles of Akt family members and the molecular mechanisms that determine Akt isoform functional specificity will be essential to elucidate the complexity of Akt regulated cellular processes and how Akt isoform-specific deregulation might contribute to disease states. Here, we summarize recent advances in understanding the roles of Akt isoforms in the regulation of metabolism and cancer, and possible mechanisms contributing to Akt isoform functional specificity.
Cadmium (Cd) and excess molybdenum (Mo) are harmful to animals, but the combined nephrotoxic mechanism of Cd and Mo in duck remains poorly elucidated. To assess joint effects of Cd and Mo on ...pyroptosis via ROS/PTEN/PI3K/AKT axis in duck renal tubular epithelial cells, cells were cultured with 3CdSO4·8H2O (4.0 μM), (NH4)6Mo7O24·4H2O (500.0 μM), MCC950 (10.0 μM), BHA (100.0 μM) and combination of Cd and Mo or Cd, Mo and MCC950 or Cd, Mo and BHA for 12 h, and the joint cytotoxicity was explored. The results manifested that toxicity of non-equitoxic binary mixtures of Mo and Cd exhibited synergic interaction. Mo or/and Cd elevated ROS level, PTEN mRNA and protein levels, and decreased PI3K, AKT and p-AKT expression levels. Simultaneously, Mo or/and Cd upregulated ASC, NLRP3, NEK7, Caspase-1, GSDMA, GSDME, IL-18 and IL-1β mRNA levels and Caspase-1 p20, NLRP3, ASC, GSDMD protein levels, increased the percentage of pyroptotic cells, LDH, NO, IL-18 and IL-1β releases as well as relative conductivity. Moreover, NLRP3 inhibitor MCC950 and ROS scavenger BHA could ameliorate the above changed factors induced by Mo and Cd co-exposure. Collectively, our results reveal that combination of Mo and Cd synergistically cause oxidative stress and trigger pyroptosis via ROS/PTEN/PI3K/AKT axis in duck tubular epithelial cells.
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•The joint toxicity of Mo and Cd was assessed in duck renal tubular epithelial cells.•There was a synergistic effect between non-equitoxic binary mixture of Mo and Cd.•Mo or/and Cd induced pyroptosis via ROS/PTEN/PI3K/AKT axis.•BHA inhibited pyroptosis co-induced by Mo and Cd via ROS/PTEN/PI3K/AKT axis.
MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The ...Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.
AKT/PKB kinases transmit insulin and growth factor signals downstream of phosphatidylinositol 3-kinase (PI3K). AKT activation involves phosphorylation at two residues, Thr308 and Ser473, mediated by ...PDK1 and the mammalian target of rapamycin complex 2 (mTORC2), respectively. Impaired AKT activation is a key factor in metabolic disorders involving insulin resistance, whereas hyperactivation of AKT is linked to cancer pathogenesis. Here, we identify the cytoplasmic NAD+-dependent deacetylase, Sirt2, as a novel AKT interactor, required for optimal AKT activation. Pharmacological inhibition or genetic down-regulation of Sirt2 diminished AKT activation in insulin and growth factor-responsive cells, whereas Sirt2 overexpression enhanced the activation of AKT and its downstream targets. AKT was prebound with Sirt2 in serum or glucose-deprived cells, and the complex dissociated following insulin treatment. The binding was mediated by the pleckstrin homology and the kinase domains of AKT and was dependent on AMP-activated kinase. This regulation involved a novel AMP-activated kinase-dependent Sirt2 phosphorylation at Thr101. In cells with constitutive PI3K activation, we found that AKT also associated with a nuclear sirtuin, Sirt1; however, inhibition of PI3K resulted in dissociation from Sirt1 and increased association with Sirt2. Sirt1 and Sirt2 inhibitors additively inhibited the constitutive AKT activity in these cells. Our results suggest potential usefulness of Sirt1 and Sirt2 inhibitors in the treatment of cancer cells with up-regulated PI3K activity and of Sirt2 activators in the treatment of insulin-resistant metabolic disorders.
AKT kinases mediate insulin signaling downstream of phosphatidylinositol-3 kinase (PI3K).
AKT binds Sirt2 in insulin-responsive cells and Sirt2 inhibition blocks AKT activation, whereas Sirt2 overexpression sensitizes cells to insulin.
Sirt2 deacetylase is an essential factor in AKT activation.
Sirt2 modulators could be useful in treatment of diseases involving AKT, such as type 2 diabetes and cancer.
Gefahren des Verstehens Angeloch, Dominic
Forum der Psychoanalyse,
12/2022, Letnik:
38, Številka:
4
Journal Article
Recenzirano
Palinurus, der Steuermann des Aeneas, begegnet in einer Episode in Vergils altrömischem Epos Aeneis dem Gott des Schlafes, Somnus, und kommt dabei auf eine so tragische wie grausame Weise zu Tode. ...Die Episode ist außerordentlich rätselhaft – unter anderem, weil sie die Frage der Schuld aufwirft, mögliche Ursachen der Schuld aber verdeckt bleiben. Wilfred Bion hat diese Episode lebenslang zu denken gegeben. An mehreren Stellen seines Werks nimmt er sie auf und spürt ihrem – mythischen – Gehalt nach, um sie schließlich zu einem „Modell“ (in Kants und Freuds Sinne) zu transformieren, anhand dessen die Gefahren von Verstehen und Deuten in der psychoanalytischen Behandlung in den Blick geraten können. Der vorliegende Beitrag nimmt zunächst eine Lektüre der Episode bei Vergil vor, um dann Bions Lektüren der Episode vorzustellen und deren Konzeption des Verstehens aus ihnen zu destillieren. Die so entstehenden epistemologischen und hermeneutischen Perspektiven werden im dritten Schritt zu einem psychologischen und geschichtsphilosophischen Ausblick zusammengebracht. Im letzten Schritt wird die Palinurus-Episode als Allegorie des Verstehens im Akt des Lesens aufgefasst, mit deren Hilfe Möglichkeiten, Methoden und Gefahren des Verstehens auch in der philologischen Arbeitssituation näher benannt werden können.
Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is a dual phosphatase with both protein and lipid phosphatase activities. PTEN was first discovered as a tumor suppressor with growth ...and survival regulatory functions. In recent years, the function of PTEN as a metabolic regulator has attracted significant attention. As the lipid phosphatase that dephosphorylates phosphatidylinositol-3, 4, 5-phosphate (PIP
), PTEN reduces the level of PIP
, a critical 2nd messenger mediating the signal of not only growth factors but also insulin. In this review, we introduced the discovery of PTEN, the PTEN-regulated canonical and nuclear signals, and PTEN regulation. We then focused on the role of PTEN and PTEN-regulated signals in metabolic regulation. This included the role of PTEN in glycolysis, gluconeogenesis, glycogen synthesis, lipid metabolism as well as mitochondrial metabolism. We also included how PTEN and PTEN regulated metabolic functions may act paradoxically toward insulin sensitivity and tumor metabolism and growth. Further understanding of how PTEN regulates metabolism and how such regulations lead to different biological outcomes is necessary for interventions targeting at the PTEN-regulated signals in either cancer or diabetes treatment.
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