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Fig. . The summarised mode of mechanism of ARVs in lung cell regulation. The FOXO-mediated transcription factors targeting the kinase regulatory activity such as p22 and p21 halts the cell cycle progression by targeted protein/ kinase/cyclin binding. Depending on the motive of the cell cycle arrest, cell death may occur. This ARV's FOXO mediated transcription reduces cell proliferation, a characteristic of anti-cancer drug. This similar mechanism may also be observed in p53 cell cycle regulation.
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The human cell cycle is a tightly regulated process with checkpoints in place to ensure genomic integrity. Cyclin/ cyclin dependent kinases (CDKs) complexes drive the progression of the cell cycle while CDK-inhibitors (CDKIs) halt the cell cycle. Deregulation of the cell cycle is a hallmark of lung cancer. TP53 and FOXO transcription factors share...
Contexts in source publication
Context 1
... protein-protein interaction (PPI) analysis of the cell cycle genes evaluated here in response to ARV treatment elucidated a series of tight interactions. Pivotal factors were identified in relation to the DNA damage response and growth arrest including GADD45A, HHS and RAD gene products and are illustrated (Fig. 5) and discussed further ...Context 2
... regulatory role of p53 on BRCA1 activity is observed by the strong and direct interaction between these two molecules, while MAD2L2 is distant from the network. The elevated expression of DNA synthesizing genes is also shown here, Fig. 5A. The deregulation of CASP3 and RAD genes/proteins and HHS1 suggests the malfunctioning of the DNA damage sensors, and the non-functioning of the effector CASP3 in the lung adenocarcinoma cells, thereby preventing them from undergoing CASP3 mediated apoptosis. Additionally, negative regulators of the cell cycle, p15 and p21 are shown to ...Context 3
... In a similar manner, LPV/r drug exposure stimulates the expression of p53 and its downstream targets such as GADD45A (DNA damage response gene) in the A549 cells, while suppressing DNA replication genes (MCM), the cell division cycle genes CDC22 and CDC25. In normal cells, most of the genes maintain a suppressed state, even post LPV/r exposure. Fig. 5B and C are a representation of the up and down regulated genes in response to ARVs. Overall, the ARV drugs stimulated DNA damage response pathways and repressed cell proliferation in both normal and cancer ...Similar publications
The human cell cycle is a tightly regulated process with checkpoints in place to ensure genomic integrity. Cyclin/cyclin dependent kinases (CDKs) complexes drive the progression of the cell cycle while CDK-inhibitors (CDKIs) halt the cell cycle. Deregulation of the cell cycle is a hallmark of lung cancer. TP53 and FOXO transcription factors share s...
Citations
... Similarly, Marima et al., (2020b) showed upregulated p53 expression followed by decreased AURKB and MAD2L2 gene expression in lung cancer A549 adenocarcinoma cells treated with protease inhibitors [152]. Furthermore, Gene Ontology (GO) analysis revealed upregulated serine/threonine kinase activity in lung cancer cells, AURKB being a member of this protein kinase family [153]. Several other studies have implicated the aberrant expression of AURKB not only in lung cancer, but also in various cancer cells. ...
Aurora Kinase B (AURKB) and Mitotic Arrest Deficient 2 Like 2 (MAD2L2) are emerging anticancer therapeutic targets. AURKB and MAD2L2 are the least well studied members of their protein families, compared to AURKA and MAD2L1. Both AURKB and MAD2L2 play a critical role in mitosis, cell cycle checkpoint, DNA damage response (DDR) and normal physiological processes. However, the oncogenic roles of AURKB and MAD2L2 in tumorigenesis and genomic instability have also been reported. DDR acts as an arbitrator for cell fate by either repairing the damage or directing the cell to self-destruction. While there is strong evidence of interphase DDR, evidence of mitotic DDR is just emerging and remains largely unelucidated. To date, inhibitors of the DDR components show effective anti-cancer roles. Contrarily, long-term resistance towards drugs that target only one DDR target is becoming a challenge. Targeting interactions between protein-protein or protein-DNA holds prominent therapeutic potential. Both AURKB and MAD2L2 play critical roles in the success of mitosis and their emerging roles in mitotic DDR cannot be ignored. Small molecule inhibitors for AURKB are in clinical trials. A few lead compounds towards MAD2L2 inhibition have been discovered. Targeting mitotic DDR components and their interaction is emerging as a potent next generation anti-cancer therapeutic target. This review focuses on AURKB and MAD2L2 prospective synergy to deregulate the p53 DDR pathway and promote favourable conditions for uncontrolled cell proliferation. This can be done by developing small molecule inhibitors for AURKB and MAD2L2, thereby targeting DDR components as anti-cancer therapeutic targets and/or targeting mitotic DDR.
Keywords: Aurora Kinase B (AURKB), Mitotic Arrest Deficient 2 Like 2 (MAD2L2), DNA damage response (DDR), Spindle Assembly Checkpoint (SAC), Small molecule inhibitor, p53.
