Cyclin-Dependent Kinases and Cyclin-Dependent Kinase Inhibitors: Detection Methods and Activity Measurements

2003 ◽  
pp. 161-170
Author(s):  
Gavin Brooks
Keyword(s):  
Kinase Inhibitors ◽  
Detection Methods ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Activity Measurements

scholarly journals Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents

1998 ◽  
Vol 143 (2) ◽  
pp. 457-467 ◽  
Author(s):  
David S. Park ◽  
Erick J. Morris ◽  
Jaya Padmanabhan ◽  
Michael L. Shelanski ◽  
Herbert M. Geller ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Sindbis Virus ◽  
Kinase Inhibitors ◽  
Sympathetic Neurons ◽  
Dominant Negative ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Dna Damaging Agents

Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cells both in vitro and in vivo. Accordingly, it has become important to understand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important role in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic and cortical neurons against DNA-damaging conditions. We show that Sindbis virus–induced expression of CKIs p16ink4, p21waf/cip1, and p27kip1, as well as DN-Cdk4 and 6, but not DN-Cdk2 or 3, protect sympathetic neurons against UV irradiation– and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent camptothecin. Finally, in consonance with our hypothesis and these results, cyclin D1–associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results suggest that postmitotic neurons may utilize Cdk4 and 6, signals that normally control proliferation, to mediate death signaling resulting from DNA-damaging conditions.

A Marine-based Meriolin (3-Pyrimidinylazaindole) Derivative (4ab) Targets PI3K/AKT /mTOR Pathway Inducing Cell Cycle Arrest and Apoptosis in Molt-4 Cells

2019 ◽  
Vol 6 (1) ◽  
pp. 33-40
Author(s):  
Gousia Chashoo ◽  
Umed Singh ◽  
Parvinder P. Singh ◽  
Dilip M. Mondhe ◽  
Ram A. Vishwakarma
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Mtor Pathway ◽  
G1 Phase ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cellular Signalling ◽  
Cycle Arrest ◽  
Cellular Apoptosis

Background: Cyclin-dependent kinases play a central role in the control of cell division and therefore it is not surprising that cancer exhibits some features that disturb the normal controls over the cell cycle. Previous studies related to the development of 3-Pyrimidinylazaindole (Meriolin) derivatives as novel Cyclin dependent kinase inhibitors highlighted 4ab as the most potent inhibitor. Objective: The main objective of the current study was to understand the mode of cell death and the effect of 4ab on major cellular networking pathways in cancer. Method: Preliminary apoptotic studies were carried out using flowcytometer and electron microscope. The effect on cellular signalling was studied via western blotting. Results: 4ab was found to inhibit the enzymatic activity of CDK2. The inhibition of CDK2 activity was found to be associated with the down-regulation of P-cdc-25 and arrest of cells in G0-G1 phase of the cell cycle in lymphoblastic leukemia cells. Further, 4ab was found to affect AKT-mToR pathway by down-regulating the expression of major proteins including P-m-TOR (2448), P110α, P-AKT (S473) and P-p-70S6K. Conclusion: Current study shows that the potent anticancer potential of 4ab is mediated via cellular apoptosis, dysregulation of mitochondrial membrane potential and arrest of G1 phase in Molt-4 cells. Further, target-based studies showed the effect of 4ab on one of the major cellular signalling pathways deregulated in cancer.

scholarly journals Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2220 ◽  
Author(s):  
Ashraf N. Abdalla ◽  
Mohamed E. Abdallah ◽  
Akhmed Aslam ◽  
Ammar Bader ◽  
Antonio Vassallo ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Cell Cycle Control ◽  
Docking Study ◽  
Cyclin Dependent Kinase ◽  
Hsp90 Inhibition ◽  
Hl60 Cells ◽  
Cyclin Dependent Kinases ◽  
Tnf Α ◽  
Caspase 7 ◽  
Client Proteins

Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA2020) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA2020, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA2020 and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA2020 propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia.

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