Involvement of PKCe in the Negative Regulation of Akt Activation Stimulated by G-CSF.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2187-2187
Author(s):  
Hong Liu ◽  
Fan Dong
Keyword(s):  
Molecular Mechanisms ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Signaling Cascades ◽  
Granulocytic Differentiation ◽  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Receptor Mutant

Abstract Granulocyte colony-stimulating factor (G-CSF) supports the proliferation, differentiation and survival of myeloid cells by stimulating the activation of several signaling cascades including the serine/threonine kinase Akt pathway. Akt activation has been shown to be important for G-CSF-induced survival and granulocytic differentiation. Although significant progresses have been made in our understanding of the molecular mechanisms by which Akt is activated, much less is known about the signaling events that negatively regulate Akt activation. Interestingly, G-CSF-induced activation of Akt was completely inhibited when myeloid 32D cells transfected with the wild type G-CSF receptor were incubated with phorbol-12-myristate 13-acetate (PMA), a PKC activator. PMA-mediated inhibition of Akt activation occurred with 5 min and lasted at least 1 hour. Previously, it has been shown that a carboxyl terminally truncated G-CSF receptor (D715), whose expression is associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia (SCN), mediates significantly prolonged Akt activation. Notably, Akt activation by G-CSF in 32D cells expressing the D715 receptor mutant was rapidly downregulated by PMA treatment. The inhibitory effect of PMA on Akt activation was abolished by pretreatment of cells with the specific PKC inhibitor GF109203X, suggesting that PKC-dependent pathway negatively regulates Akt activation. Ro-31-7549, a specific inhibitor of PKCe, also abrogated PMA-mediated inhibition of Akt activation whereas rottlerin and Go6976, inhibitors of PKCd and PKC a/bI,, respectively, displayed no effect. Together, these results identified PKCe as being critically involved in PMA-mediated inhibition of Akt activation. Experiments are currently under way to determine the mechanism by which PKCe downregulates Akt activation and the role of PKCe in the regulation of cell proliferation, differentiation and survival in response to G-CSF.

scholarly journals The Hippo Pathway and YAP Signaling: Emerging Concepts in Regulation, Signaling, and Experimental Targeting Strategies With Implications for Hepatobiliary Malignancies

2020 ◽  
Vol 20 (1) ◽  
pp. 67-74 ◽  
Author(s):  
Nathan Werneburg ◽  
Gregory J. Gores ◽  
Rory L. Smoot
Keyword(s):  
Hippo Pathway ◽  
Current Data ◽  
Signaling Cascades ◽  
Serine Threonine Kinase ◽  
Feed Forward ◽  
Regulatory Pathways ◽  
Threonine Kinase ◽  
The Hippo Pathway ◽  
Hepatic Malignancies

The Hippo pathway and its effector protein YAP (a transcriptional coactivator) have been identified as important in the biology of both hepatocellular carcinoma and cholangiocarcinoma. First identified as a tumor suppressor pathway in Drosophila, the understanding of the mammalian YAP signaling and its regulation continues to expand. In its “on” function, the canonical regulatory Hippo pathway, a well-described serine/threonine kinase module, regulates YAP function by restricting its subcellular localization to the cytoplasm. In contrast, when the Hippo pathway is “off,” YAP translocates to the nucleus and drives cotranscriptional activity. Given the role of Hippo/YAP signaling in hepatic malignancies, investigators have sought to target these molecules; however, standard approaches have not been successful based on the pathways’ negative regulatory role. More recently, additional regulatory mechanisms, such as tyrosine phosphorylation, of YAP have been described. These represent positive regulatory events that may be targetable. Additionally, several groups have identified potentiating feed-forward signaling for YAP in multiple contexts, suggesting other experimental therapeutic approaches to interrupt these signaling loops. Herein we explore the current data supporting alternative YAP regulatory pathways, review the described feed-forward signaling cascades that are YAP dependent, and explore targeting strategies that have been employed in preclinical models of hepatic malignancies.

scholarly journals Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer.

2021 ◽  
Author(s):  
Amelia U. Schirmer ◽  
Lucy M. Driver ◽  
Megan T. Zhao ◽  
Carrow I. Wells ◽  
Julie E. Pickett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

scholarly journals In Situ Hybridization Analysis of ZPK Gene Expression During Murine Embryogenesis

1997 ◽  
Vol 45 (1) ◽  
pp. 107-118 ◽  
Author(s):  
André Nadeau ◽  
Gilles Grondin ◽  
Richard Blouin
Keyword(s):  
In Situ Hybridization ◽  
Northern Blot Analysis ◽  
Spatial And Temporal Patterns ◽  
Serine Threonine Kinase ◽  
Teratocarcinoma Cell ◽  
Threonine Kinase ◽  
Cell Lineages ◽  
Polymerase Chain

ZPK is a recently described protein serine/threonine kinase that has been originally identified from a human teratocarcinoma cell line by the polymerase chain reaction and whose function in signal transduction has not yet been elucidated. To investigate the potential role of this protein kinase in developmental processes, we have analyzed the spatial and temporal patterns of expression of the ZPK gene in mouse embryos of different gestational ages. Northern blot analysis revealed a single mRNA species of about 3.5 KB from Day 11 of gestation onwards. In situ hybridization studies demonstrated strong expression of ZPK mRNA in brain and in a variety of embryonic organs that rely on epithelio-mesenchymal interactions for their development, including skin, intestine, pancreas, and kidney. In these tissues, the ZPK mRNA was localized primarily in areas composed of specific types of differentiating cells, and this expression appeared to be upregulated at a time concomitant with the onset of terminal differentiation. Taken together, these observations raise the possibility that the ZPK gene product is involved in the establishment and/or maintenance of a fully cytodifferentiated state in a variety of cell lineages.

scholarly journals ROLE OF SERIN/ THREONINE KINASE INHIBITOR IN THERAPY NON-ALCOHOLIC STEATOHEPATITIS AND ALCOHOLIC HEPATITIS

2019 ◽  
Vol 6 (3) ◽  
pp. 101-109
Author(s):  
Novriantika Lestari
Keyword(s):  
Signal Transduction ◽  
Liver Fibrosis ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Binding Activity ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Receptor Binding Activity ◽  
Marked Accumulation

Liver fibrosis is a reversible response to a wound healing with marked accumulation of extracellular matrix which caused by injury to the liver. Liver fibrosis can be caused by various factors including alcohol and non-alcohol steatohepatitis. The process of fibrosis serves to localize the inflammation during chronic exposure. The hepatic stem cell (HSC) has a key role in the pathogenesis of liver fibrosis. The HSC activation is characterized by increased profibrogenic mediators including members of the TGF-? superfamily. In order to enable signal transduction, the mediator needs to bind to its receptors. The serine/ threonine kinase receptor is a receptor that binds to the TGF-? superfamily ligand, including TGF-?, BMP, activin and other mediators. The ligand receptor-binding activity will stimulate signal transduction that will translocate into the nucleus and phosphorylate various transcription factors that play a role in cell proliferation, differentiation, or apoptosis. There is currently no standard therapy for liver fibrosis. Based on the central role of the serine/ threonine kinase receptor in the pathogenesis of liver fibrosis, it is thought that the use of serine/ threonine kinase inhibitors is a promising therapy.

scholarly journals Molecular mechanisms of control of differentiation of regulatory t-lymphocytes by exogenous melatonin

2019 ◽  
Vol 484 (2) ◽  
pp. 224-227
Author(s):  
N. S. Glebezdina ◽  
A. A. Olina ◽  
I. V. Nekrasova ◽  
E. M. Kuklina
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Inhibitory Effect ◽  
The Body ◽  
Membrane Receptors ◽  
Cell Subpopulation ◽  
Exogenous Melatonin ◽  
Regulatory T Lymphocytes ◽  
Treg Differentiation

We investigated the role of epiphyseal hormone melatonin in the differentiation of naive CD4+T cells into regulatory T cells (Treg). The hormone at physiological and pharmacological concentrations inhibited Treg differentiation, decreasing both the proportion of CD4+FOXP3+ cells in the culture and the level of TGF‑β, the key cytokine for this T cell subpopulation. The inhibitory effect of exogenous melatonin was due to its interaction with the membrane receptors MT1 and MT2. At the same time, the signals realized through RORa — the nuclear receptor for melatonin — stimulated Treg formation; however, they were considerably weaker than the signals from the membrane receptors and were overlapped by the latter. Since the Treg subpopulation plays an important role in physiological and pathological processes in the body, the revealed effects of melatonin should be taken into account in its therapeutic use.

scholarly journals Neurogenesis and Increase in Differentiated Neural Cell Survival via Phosphorylation of Akt1 after Fluoxetine Treatment of Stem Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Anahita Rahmani ◽  
Danial Kheradmand ◽  
Peyman Keyhanvar ◽  
Alireza Shoae-Hassani ◽  
Amir Darbandi-Azar
Keyword(s):  
Survival Rate ◽  
Cell Survival ◽  
Neural Cell ◽  
Neural Cells ◽  
Chain Reaction ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Fluoxetine Treatment ◽  
Polymerase Chain

Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI). Its action is possibly through an increase in neural cell survival. The mechanism of improved survival rate of neurons by FLX may relate to the overexpression of some kinases such as Akt protein. Akt1 (a serine/threonine kinase) plays a key role in the modulation of cell proliferation and survival. Our study evaluated the effects of FLX on mesenchymal stem cell (MSC) fate and Akt1 phosphorylation levels in MSCs. Evaluation tests included reverse transcriptase polymerase chain reaction, western blot, and immunocytochemistry assays. Nestin, MAP-2, andβ-tubulin were detected after neurogenesis as neural markers. TenμM of FLX upregulated phosphorylation of Akt1 protein in induced hEnSC significantly. Also FLX did increase viability of these MSCs. Continuous FLX treatment after neurogenesis elevated the survival rate of differentiated neural cells probably by enhanced induction of Akt1 phosphorylation. This study addresses a novel role of FLX in neurogenesis and differentiated neural cell survival that may contribute to explaining the therapeutic action of fluoxetine in regenerative pharmacology.

scholarly journals Role of diamine oxidase during the treatment of tumour-bearing mice with combinations of polyamine anti-metabolites

1983 ◽  
Vol 212 (3) ◽  
pp. 895-898 ◽  
Author(s):  
A Kallio ◽  
J Jänne
Keyword(s):  
Diamine Oxidase ◽  
Potent Inhibitor ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Tumour Cells ◽  
Adenosylmethionine Decarboxylase ◽  
Growth Inhibitory ◽  
Sequential Combination ◽  
Marked Accumulation

Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone.

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