Human CDK18 promotes replication stress signaling and genome stability

Barone, Giancarlo; Staples, Christopher J.; Ganesh, Anil; Patterson, K.; Bryne, Dominic P.; Myers, Katie; Patil, Abhijit A.; Eyers, Patrick A.; Skehel, J. Mark; Collis, Spencer J.

doi:10.1093/nar/gkw615

Cited by 43 publications

(47 citation statements)

References 57 publications

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“…Dysregulation of CDKs results in imbalance in apoptosis and proliferation which is a hallmark of a cancer. Loss of CDK18 may lead to dysregulation of cell-cycle check-point increasing genomic instability and development of gastric cancer [ 32 ]. Another gene that was related to GC identified in this study is PR domain containing 16 ( PRDM16 ) which is function as a zinc finger transcription factor regulates chromatin function and different transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH)

Bibi¹,

Ali²,

Naseer³

et al. 2018

PLoS ONE

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BackgroundThe present study was conducted to discover genetic imbalances such as DNA copy number variations (CNVs) associated with gastric cancer (GC) and to examine their association with different genes involved in the process of gastric carcinogenesis in Saudi population.MethodsFormalin-fixed paraffin-embedded (FFPE) tissues samples from 33 gastric cancer patients and 15 normal gastric samples were collected. Early and late stages GC samples were genotyped and CNVs were assessed by using Illumina HumanOmni1-Quad v.1.0 BeadChip.ResultsCopy number gains were more frequent than losses throughout all GC samples compared to normal tissue samples. The mean number of the altered chromosome per case was 64 for gains and 40 for losses, and the median aberration length was 679115bp for gains and 375889bp for losses. We identified 7 high copy gain, 52 gains, 14 losses, 32 homozygous losses, and 10 copy neutral LOHs (loss of heterozygosities). Copy number gains were frequently detected at 1p36.32, 1q12, 1q22, 2p11.1, 4q23-q25, 5p12-p11, 6p21.33, 9q12-q21.11, 12q11-q12, 14q32.33, 16p13.3, 17p13.1, 17q25.3, 19q13.32, and losses at 1p36.23, 1p36.32, 1p32.1, 1q44, 3q25.2, 6p22.1, 6p21.33, 8p11.22, 10q22.1, 12p11.22, 14q32.12 and 16q24.2. We also identified 2 monosomy at chromosome 14 and 22, 52 partially trisomy and 22 whole chromosome 4 neutral loss of heterozygosities at 13q14.2-q21.33, 5p15.2-p15.1, 5q11.2-q13.2, 5q33.1-q34 and 3p14.2-q13.12. Furthermore, 11 gains and 2 losses at 1p36.32 were detected for 11 different GC samples and this region has not been reported before in other populations. Statistical analysis confirms significant association of H. pylori infection with T4 stage of GC as compare to control and other stages.ConclusionsWe found that high frequency of copy number gains and losses at 1p36.23, 1p32.1, 1p36.32, 3q25.2, 6p21.33 and 16q24.2 may be common events in gastric cancer. While novel CNVs at 1p36.32 harbouring PRDM16, TP73 and TP73-AS1 genes showed 11 gains and 2 losses for 11 different GC cases and this region is not reported yet in Database of Genomic Variants may be specific to Saudi population.

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Section: Discussionmentioning

confidence: 99%

Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH)

Bibi¹,

Ali²,

Naseer³

et al. 2018

PLoS ONE

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“…Therefore, we aimed to characterize its function in the regulation of AQP2. It has been shown that CDK18 may be involved in Alzheimer's disease, [50,51] in the Ataxia Telangiectasia and RAD3-related (ATR)-mediated response to single strand DNA and in cell cycle control [52,53]. Indeed, its role in cell cycle control is in line with the by 30% reduced MCD4 cell number if CDK18 was knocked down ( Table 1).…”

Section: Knockdown Of Cdk18 Inhibits the Camp-induced Redistributionmentioning

confidence: 90%

Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP

Dema

Faust

Lazarow

et al. 2020

Cells

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Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure.

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“…It is expressed in neuronal tissue and there is evidence that it plays a role in the progression of Alzheimer's disease, since it is found in high concentrations in pathological tissue, and is proposed to modulate Tau phosphorylation (Herskovits and Davies 2006). More recently, it has been shown to prevent accumulated DNA damage and genome instability in response to replication stress (Barone et al 2016).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Human CDK18 promotes replication stress signaling and genome stability

Cited by 43 publications

References 57 publications

Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH)

Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH)

Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP

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

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