Differential expression of cyclin-dependent kinases in the adult human retina in relation to CDK inhibitor retinotoxicity

Abstract

Cyclin-dependent kinases (CDKs) are a family of kinases associated predominantly with cell cycle control, making CDK inhibitors interesting candidates for anti-cancer therapeutics. However, retinal toxicity (loss of photoreceptors) has been associated with CDK inhibitors, including the pan-CDK inhibitor AG-012896. The purpose of this research was to use a novel planar sectioning technique to determine CDK expression profiles in the ex vivo human retina with the aim of identifying isoforms responsible for CDK retinotoxicity. Four CDK isoforms (CDK11, 16, 17 and 18) were selected as a result of IC 50 data comparing neurotoxic (AG-012986 and NVP-1) and non-neurotoxic (dinaciclib and NVP-2) CDK inhibitors, with IC 50 s at CDK11 showing a clear difference between the neurotoxic and non-neurotoxic drugs. CDK11 was maximally expressed in the photoreceptor layer, whereas CDK16, 17 and 18 showed maximal expression in the inner nuclear layer. CDK5 (an isoform associated with retinal homeostasis) was maximally expressed in the retinal ganglion cell layer. Apart from CDK18, each isoform showed expression in the photoreceptor layer. The human Müller cell line MIO-M1 expressed CDK5, 11, 16 and 17 and AG-01298 (0.02-60 µM) caused a dose-dependent increase in MIO-M1 cell death. In conclusion, CDK11 appears the most likely candidate for mediation of photoreceptor toxicity. RNA profiling can be used to determine the distribution of genes of interest in relation to retinal toxicity in the human retina.

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

“…We next focused on the effect of TPD7 treatment on cell cycle progression and the results showed that TPD7 mainly blocked the cell cycle progression at G2/M phase and partially at G1 phase (Figure ). Previously, cyclin‐dependent kinase (CDK) and cyclins function as dynamic regulators of cell cycle progression . CyclinB1 was associated with the G2/M checkpoint control and could form a complex by binding with CDC2, which takes an important part in G2/M phase transition .…”

“…Previously, cyclin-dependent kinase (CDK) and cyclins function as dynamic regulators of cell cycle progression. 33 CyclinB1 was associated with the G2/M checkpoint control and could form a complex by binding with CDC2, which takes an important part in G2/M phase transition. 34 And, it was well recognized that CDC2, cyclinD1 and cyclinE are critical molecules in the regulation of cells from G1 phase into S phase.…”

circRNA_141539 can serve as an oncogenic factor in esophageal squamous cell carcinoma by sponging miR-4469 and activating CDK3 gene

“…A previous study [ 21 ] reported that miR-4469 was significantly down-regulated in breast cancer and that miR-4469 suppressed breast cancer metastasis by inhibiting the Wnt/β-catenin pathway. CDK3 is a member of the cyclin-dependent kinase family and is directly involved in cell cycle regulation for G1 exit and S entry [ 22 , 23 ]. The activation of CDK3 leads to G1 arrest and serves an important role in cell proliferation and malignant transformation [ 24 ].…”

On the Sensitivity of the Virion Envelope to Lipid Peroxidation

“…Although some cellular proteins are required for the replication of many viruses, an antiviral inhibiting them should result in no toxic effects to the entire organism. Consequently, no drug targeting these proteins has been developed into an antiviral ( 5 – 9 ), even though many cellular proteins are targeted by drugs developed for non-infectious diseases, including the cyclin-dependent kinases (CDK) ( 10 , 11 ), which are involved in the replication of many unrelated viruses.…”