The cell proliferation protein 123 (CDC123) is involved in the synthesis of the eukaryotic initiation factor 2 (eIF2), which regulates eukaryotic translation. Although CDC123 is considered a candidate oncogene in breast cancer, its expression and role in Hepatocellular Carcinoma (HCC) remain unknown. Herein, we obtained the CDC123 RNA-seq and clinical prognostic data from the TCGA database. The mRNA level revealed that CDC123 was highly expressed in HCC patients, and Kaplan-Meier analysis implied better prognoses in HCC patients with low CDC123 expression (P < 0.001). The multivariate Cox analysis revealed that the CDC123 level was an independent prognostic factor (P < 0.001). We further confirmed a high CDC123 expression in HCC cell lines. Additionally, we found that CDC123 knockdown in HCC cell lines significantly inhibited cellular proliferation, invasion, and migration. Moreover, CDC123 was co-expressed with the CDK5 Regulatory Subunit-Associated Protein 1 Like 1 (CDKAL1), whose mRNA level was decreased after silencing CDC123. Therefore, we hypothesized that CDC123 promotes HCC progression by regulating CDKAL1.

Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.
Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).
We identified 6 genome-wide significant (P < 5 × 10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.
Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.

Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5\' untranslated region (5\'UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2 -terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

N6-methyladenosine (m6A) modification is the most common mRNA modification that is considered a new layer of mRNA epigenetic regulation. Demethylase fat mass and obesity-associated protein (FTO) are important in the dynamic regulation of m6A, but their role in gastric cancer (GC) is not fully understood. This study revealed that FTO and CDKAL1 were up-regulated in GC cells and tissue. CDKAL1 is the downstream target of FTO-mediated m6A modification, with FTO promoting GC cell proliferation through CDKAL1 and inducing mitochondrial fusion, eventually causing GC chemoresistance. In conclusion, FTO contributes to the increasing resistance of GC cells to 5-fluorouracil (5-Fu) by upregulating CDKAL1 and inducing mitochondrial fusion.

BACKGROUND: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) encodes a tRNA modifying enzyme involved in the proper protein translation and regulation of insulin production encoded by the CDKL gene. Sequence variations in the CDKAL1 gene lead to the misreading of the Lys codon in proinsulin, resulting in decreased glucose-stimulated proinsulin production. Various polymorphic sequence variants of the CDKAL1 gene such as rs7754840, rs7756992, rs9465871, and rs10946398 are reported to be associated with type 2 diabetes mellitus and gestational diabetes mellitus (GDM) incidence. One of these single nucleotide polymorphisms i.e., rs10946398 has been reported to impact the risk of GDM and its outcomes in pregnant women of different ethnicities i.e., Egypt, Chinese, Korean, Indian, Arab, and Malaysian. Numerous findings have shown that rs10946398 overturns the regulation of CDKAL1 expression, resulting in decreased insulin production and elevated risk of GDM. However, there is no data regarding rs10946398 genotype association with GDM incidence in our population.
METHODS: In this study, 47 GDM patients and 40 age-matched controls were genotyped for rs10946398 CDKAL1 variant using Tetra primer Amplification Refractory Mutation System Polymerase Chain Reaction (Tetra ARMS-PCR).
RESULTS: Analysis of the results showed the significant association of the C allele of CDKAL1 SNP rs10946398 (χ2 = 0.02 p = 0.001) with the risk of GDM development. Conclusively, the results support the role of SNP i.e., rs10946398 of CDKAL1 gene in GDM development in Pakistani female patients. However, future large-scale studies are needed to functionally authenticate the role of variant genotypes in the disease pathogenesis and progression.

BACKGROUND: Interactions between genetic, metabolic, and environmental factors lead to gestational diabetes mellitus (GDM). We aimed to examine interactive effects of cyclin-dependent kinase 5 regulatory subunit-associated protein1-like 1(CDKAL1) rs7747752 polymorphism with low serum levels of L-carnitine, choline, and betaine for GDM.
METHODS: A nested case-control study of 207 GDM women and their one-to-one, age-matched controls was organized from a prospective cohort of pregnant women in Tianjin, China. Conditional logistic regressions were used to test associations between CDKAL1 rs7747752 and serum levels of L-carnitine, choline, and betaine, and the risk of GDM. Additive interactions were performed to examine interactive effects of rs7747752 and low serum levels of L-carnitine, choline, and betaine on the risk of GDM.
RESULTS: The CDKAL1 rs7747752 G > C was associated with GDM in additive, dominant, and recessive model (P <0.05). The rs7747752 CC genotype enhanced the OR of L-carnitine ≤ vs. > 150 nmol/mL for GDM from 6.14 (2.61-14.4) to 19.6 (5.65-68.1) and the OR of choline ≤ vs. > 110 nmol/mL from 2.37 (1.07-5.28) to 12.1 (3.22-45.6), with significant additive interactions. Similarly, CG genotype also enhanced the OR of L-carnitine ≤ vs. > 150 nmol/mL for GDM from 4.70 (2.01-11.0) to 11.4 (3.98-32.9), with a significant additive interaction. However, the additive interaction between rs7747752 and betaine ≤ 200 nmol/mL on the risk of GDM was not significant.
CONCLUSIONS: The CC or CG genotype carriers in rs7747752 of CDKAL1 who have a low serum level of L-carnitine or choline are at a particular high risk of GDM. Randomized controlled trials are warranted to test the effect of supplement of L-carnitine or choline on the risk of GDM in the high-risk group.

Diabetes Mellitus, being a polygenic disorder, have a set of risk genes involved in the onset of the insulin resistance, obesity and impaired insulin synthesis. Recent genome wide association studies (GWAS) shows the intimacy of CDK5 regulatory subunit Associated protein 1-Like 1 (Cdkal1) with the pathophysiology of the diabetes mellitus and its complications, although the exact molecular relation is still unknown. In this short review, we have summarized all the diverse biological roles of Cdkal1 in relation to the onset of diabetes mellitus. Variations in the Cdkal1 transcript are responsible for the accumulation of misfolded insulin and thus generating oxidative and ER stress in the pancreatic β-cells, leading to their destruction. Recent studies have shown that Cdkal1 has an intrinsic thiomethyl transferase activity, which is essential for proper posttranslational processing of pre-proinsulin to produce mature insulin. Moreover, Cdkal1 has also been claimed as an endogenous inhibitor of cdk5, which prevents the cdk5-induced interruption in insulin synthesis through PDX1 translocation from nucleus to cytosol. Recent clinical studies have identified the risk single nucleotide polymorphisms (SNPs) of Cdkal1 as one of the root causes for the onset of diabetic complications. To the best of our knowledge, it is the first comprehensive review which elaborates most of the potential Cdkal1-dependent molecular mechanisms studied yet. In this review, we present a compiled and concise summary about all the diverse roles of Cdkal1 in the context of type 2 diabetes mellitus and its associated complications. This review will be helpful to target Cdkal1 as a potential option for the management of type 2 diabetes mellitus in future.
UNASSIGNED:

The study aimed to explore additive interactions of CDKAL1 rs7747752 and GUDCA/DCA for GDM risk and whether the interactive effects on the risk of GDM was mediated via increasing lysophosphatidylcholines (LPC) 18:0 and/or saturated fatty acid (SFA) 16:0.
A 1:1 age-matched study nested in a prospective cohort of pregnant women (207 pairs) was organized in Tianjin, China. Additive interactions were used to test interaction effects while mediation analyses and Sobel tests were used to test mediation effects of LPC18:0 and SFA16:0 between copresence of rs7747752 and low GUDCA/DCA, and GDM risk.
The CDKAL1 rs7747752 was associated with GDM (P<0.05). The rs7747752 C polymorphism markedly enhanced ORs of low GUDCA from 4.04 (0.72-22.8) to 9.02 (1.63-49.7) and low DCA from 1.67 (0.68-4.11) to 4.24 (1.84-9.76), both with significant additive interactions. Further adjustment for LPC18:0 attenuated the interactive effects of rs7747752 and low DCA, with a significant mediation effect (P=0.003). High SFA16:0 did not mediate the interactive effects of rs7747752 and low DCA/GUDCA on GDM risk.
The CDKAL1 rs7747752 C carrier status and low GUDCA/DCA had significant additive interactions on the risk of GDM with the effect from interaction with DCA being partially mediated via increasing LPC18:0.

BACKGROUND: Association of single nucleotide polymorphisms (SNP) rs7756992 A/G and rs7754840 G/C of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene with the susceptibility of gestational diabetes mellitus (GDM) has been studied in a group of Bangladeshi women.
METHODS: In this case-control study, 212 GDM patients and 256 control subjects were genotyped for rs7756992 and rs7754840 by PCR-RFLP and TaqMan™ allelic discrimination assay method respectively. Genotyping results were confirmed by DNA sequencing and replicated TaqMan™ assay. The odds ratios and their 95% confidence interval were calculated by logistic regression to determine the associations between genotypes and GDM.
RESULTS: The genotype frequencies of rs7756992-AA/AG/GG in the GDM group and the control group were 37%/48%, 53%/45%, 10%/7% and those of rs7754840-CC/CG/GG were 51%/55%, 40.1%/39.8%, 9%/5% respectively. Under dominant and log additive models rs7756992 was revealed significantly associated with GDM after being adjusted for family history of diabetes (FHD) and gravidity. Conversely, rs7754840 was significantly associated (P = 0.047) with GDM only under the recessive model after the same adjustment. The risk allele frequency of both SNPs was higher in the GDM group but significantly (P = 0.029) increased prevalence was observed in the rs7756992 G allele. When positive FHD and risk alleles of these SNPs were synergistically present in any pregnant woman, the chance of developing GDM was augmented by many folds. The codominant model revealed 2.5 and 2.1 folds increase in odds by AG (rs7756992) and GC (rs7754840) genotypes and 3.7 and 4.5 folds by GG (rs7756992) and CC (rs7754840) genotypes respectively. A significant 2.7 folds (P = 0.038) increase in odds of GDM resulted from the interaction of rs7756992 and family history of diabetes under the dominant model. The cumulative effect of multigravidity and risk alleles of these SNPs increased the odds of GDM more than 1.5 folds in different genotypes.
CONCLUSIONS: This study not only revealed a significant association between rs7756992 and rs7754840 with GDM but also provided the possibility as potential markers for foretelling about GDM and type 2 diabetes mellitus in Bangladeshi women.

Background: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients. Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models. Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103-1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073-1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056-1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265-1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187-1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155-1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167-1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model. Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.