Phosphatase and tensin homolog (PTEN; MMAC1; TEP1); casein kinase 2 (CK2)

Background: Non-Hodgkin's lymphomas (NHL), derived from B- or T-cell, consist of a heterogeneous group of malignant lymphoproliferative disorders. Knockdown of Casein kinase 2 interacting protein-1 (CKIP-1) in NHL promoted cell proliferation and inhibited apoptosis via enhancing phosphorylated Protein Kinase B (PKB or AKT) expression. Statins are the class of drugs that inhibit the ratelimiting step of the mevalonate pathway, which is essential for the biosynthesis of various compounds, including cholesterol. Also, statins have anticancer properties being mediated by different mechanisms. Methods: A search on databases like Scopus and PubMed with keywords such as statin and non- Hodgkin's lymphomas was performed and Kyoto Encyclopedia of Genes and Genomes (KEGG) website was used to evaluate and reconfirm the involved cellular signaling pathway. Results: CKIP-1 is involved in the regulation of cell proliferation and apoptosis while plays an important role in many cancers. We can hypothesize that statins may increase the expression levels of CKIP-1 which could contribute to the reductions in phospho-AKT level. Hence, they may ameliorate the NHL patients via suppressing AKT phosphorylation and increasing CKIP- expression. Conclusion: Present review confirms the positive effect of statins on NHL by increasing CKIP-1 and reducing cell proliferation, subsequently.

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Novel Anthraquinone Derivatives as Dual Inhibitors of Topoisomerase 2 and Casein Kinase 2: In Silico Studies, Synthesis and Biological Evaluation on Leukemic Cell Lines

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180423111309 ◽

2019 ◽

Vol 18 (11) ◽

pp. 1551-1562 ◽

Cited By ~ 4

Author(s):

Abbas Kabir ◽

Kalpana Tilekar ◽

Neha Upadhyay ◽

C.S. Ramaa

Keyword(s):

Cell Cycle ◽

Cell Line ◽

Cell Lines ◽

Biological Evaluation ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Cell Cycle Analysis ◽

Protein Targets ◽

Topoisomerase 2 ◽

Dual Inhibitors

Background: Cancer being a complex disease, single targeting agents remain unsuccessful. This calls for “multiple targeting”, wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2. Objective: With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve the anti-proliferative effects. Methods: Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis. Results: The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1 phase. Conclusion: We have successfully designed, synthesized, purified and structurally characterized 1- acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.

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High Throughput Screen Identifies the DNMT1 (DNA Methyltransferase-1) Inhibitor, 5-Azacytidine, as a Potent Inducer of PTEN (Phosphatase and Tensin Homolog)

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314458 ◽

2020 ◽

Vol 40 (8) ◽

pp. 1854-1869

Author(s):

Keith A. Strand ◽

Sizhao Lu ◽

Marie F. Mutryn ◽

Linfeng Li ◽

Qiong Zhou ◽

...

Keyword(s):

Protein Expression ◽

High Throughput ◽

Knockout Mice ◽

Vascular Remodeling ◽

Dna Methyltransferase ◽

Dna Methyltransferase 1 ◽

Protective Effects ◽

High Throughput Screen ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

Objective: Our recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Ang II (angiotensin II)-induced pathological vascular remodeling, suggesting that pharmacological PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Approach and Results: To identify novel PTEN activators, we conducted a high-throughput screen using a fluorescence based PTEN promoter-reporter assay. After screening ≈3400 compounds, 11 hit compounds were chosen based on level of activity and mechanism of action. Following in vitro confirmation, we focused on 5-azacytidine, a DNMT1 (DNA methyltransferase-1) inhibitor, for further analysis. In addition to PTEN upregulation, 5-azacytidine treatment increased expression of genes associated with a differentiated SMC phenotype. 5-Azacytidine treatment also maintained contractile gene expression and reduced inflammatory cytokine expression after PDGF (platelet-derived growth factor) stimulation, suggesting 5-azacytidine blocks PDGF-induced SMC de-differentiation. However, these protective effects were lost in PTEN-deficient SMCs. These findings were confirmed in vivo using carotid ligation in SMC-specific PTEN knockout mice treated with 5-azacytidine. In wild type controls, 5-azacytidine reduced neointimal formation and inflammation while maintaining contractile protein expression. In contrast, 5-azacytidine was ineffective in PTEN knockout mice, indicating that the protective effects of 5-azacytidine are mediated through SMC PTEN upregulation. Conclusions: Our data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.

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Phosphorylation of glycogen synthase by cyclic AMP-independent casein kinase-2 from rabbit skeletal muscle.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)81101-8 ◽

1982 ◽

Vol 257 (6) ◽

pp. 3236-3242

Author(s):

K P Huang ◽

E Itarte ◽

T J Singh ◽

A Akatsuka

Keyword(s):

Skeletal Muscle ◽

Cyclic Amp ◽

Glycogen Synthase ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Rabbit Skeletal Muscle

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miR-139-5p promotes neovascularization in diabetic retinopathy by regulating the phosphatase and tensin homolog

Archives of Pharmacal Research ◽

10.1007/s12272-021-01308-8 ◽

2021 ◽

Vol 44 (2) ◽

pp. 205-218

Author(s):

Zhongwei Zhang ◽

Caiping Song ◽

Tao Wang ◽

Lei Sun ◽

Ling Qin ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

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Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer’s disease

Cell Death and Disease ◽

10.1038/s41419-021-04062-3 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Barbara Bettegazzi ◽

Laura Sebastian Monasor ◽

Serena Bellani ◽

Franca Codazzi ◽

Lisa Michelle Restelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Activity ◽

Neurodegenerative Disorder ◽

Brain Slices ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Bace1 Expression

AbstractAlzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

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The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22041525 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1525

Author(s):

Chunling Huang ◽

Ji Bian ◽

Qinghua Cao ◽

Xin-Ming Chen ◽

Carol A. Pollock

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Kidney Diseases ◽

Mitochondrial Protein ◽

Physiological Role ◽

Close Link ◽

Promising Alternative ◽

Diabetic Kidney ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.

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Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN

Cell Death and Disease ◽

10.1038/s41419-021-03514-0 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Mi Tian ◽

Jingjing Wang ◽

Shangming Liu ◽

Xinyun Li ◽

Jingyuan Li ◽

...

Keyword(s):

Glucose Metabolism ◽

Hepatic Steatosis ◽

Chow Diet ◽

Alcoholic Fatty Liver ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Pten Mrna ◽

Normal Chow ◽

Mice Liver

AbstractThe liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuRLKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3′ untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuRLKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

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