scholarly journals Chronic cadmium exposure aggravates malignant phenotypes of nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway via hypermethylation of the casein kinase 1α promoter

2018 ◽  
Vol Volume 11 ◽  
pp. 81-93 ◽  
Author(s):  
Lin Peng ◽  
Yi-Teng Huang ◽  
Fan Zhang ◽  
Jiong-Yu Chen ◽  
Xia Huo
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Casein Kinase ◽  
Cadmium Exposure ◽  
Beta Catenin ◽  
Casein Kinase 1 ◽  
Casein Kinase 1 Alpha

Casein kinase 1 alpha expression determines beta-catenin protein level and survival of melanoma cells

2006 ◽  
Vol 16 (Supplement 1) ◽  
pp. S98
Author(s):  
T. Sinnberg ◽  
C. Garbe ◽  
F. Meier ◽  
B. Schittek
Keyword(s):  
Protein Level ◽  
Melanoma Cells ◽  
Casein Kinase ◽  
Beta Catenin ◽  
Casein Kinase 1 ◽  
Casein Kinase 1 Alpha

Casein Kinase 1 Alpha Maintains Normal and Leukemic Stem Cells by Regulating p53 Activity

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 209-209
Author(s):  
Marcus Järås ◽  
Peter G. Miller ◽  
Lisa Chu ◽  
Rebekka K. Schneider ◽  
Rishi V Puram ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Casein Kinase ◽  
Leukemia Cells ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Leukemic Stem Cells ◽  
Casein Kinase 1 ◽  
Donor Cells ◽  
Casein Kinase 1 Alpha

Abstract Abstract 209 In order to identify novel approaches to the targeting of acute myeloid leukemia (AML), we performed a pooled in vivo shRNA screen on murine leukemic stem cells (LSCs) targeting factors related to Wnt-signaling. We found that silencing of casein kinase 1 alpha (Csnk1a1), a serine-threonine kinase and a critical negative regulator of beta catenin, dramatically depleted murine LSCs in vivo. This is a surprising result since beta catenin is essential for MLL-AF9 AML. Validation experiments with shRNA vectors co-expressing GFP recapitulated the result from the pooled screen and confirmed efficient knockdown of both the Csnk1a1 transcript and protein. To rule out off-target effects of the Csnk1a1 shRNAs, we co-expressed the shRNAs with a Csnk1a1 cDNA mutated at the shRNA binding sites, and observed a complete rescue of the proliferative defect. Additionally, we demonstrated that a kinase dead form of Csnk1a1(D136N) failed to rescue this proliferation defect. These results indicate the specific effect of these hairpins on Csnk1a1 function in leukemia cells. The role of Csnk1a1 in normal hematopoietic stem and progenitor cells (HSPCs) is not known. We introduced the Csnk1a1 shRNA vectors into HSPCs and followed GFP over time in a bone marrow transplantation setting. Over a 24-week period, we observed a 3–4 fold depletion of GFP positive donor cells with two independent Csnk1a1 shRNAs compared to control. In contrast, the same shRNAs resulted in a 20–25 fold depletion of leukemia cells in vivo over a 2-week time period, suggesting that leukemia cells are selectively dependent on Csnk1a1. To more rigorously study Csnk1a1 in hematopoiesis, we generated a Csnk1a1 conditional knockout mouse (loxP sites flanking critical exon 3) and crossed it with the Mx1-cre mouse, allowing for hematopoietic specific inducible Csnk1a1 excision. In competitive bone marrow transplantations, Csnk1a1(−/−) donor cells exhibited a severe competitive disadvantage resulting in a 20-fold depletion of donor cells over a 12-week period. Interestingly, Csnk1a1(−/−) donor cells were devoid of myeloid lineage cells, suggesting that Csnk1a1 is particularly important for the generation or survival of myeloid cells. Moreover, in line with our shRNA results, we found that Csnk1a1(−/−) cells were resistant to MLL-AF9 mediated transformation, demonstrating that Csnk1a1 is essential also for leukemia initiation. To identify critical targets of Csnk1a1, we performed gene expression profiling of Csnk1a1 silenced cells. We identified enrichment of a p53 signature using Gene Set Enrichment Analysis (FDR= 0.001). Induction of p53 and its target p21 was confirmed by western blots in both Csnk1a1 silenced leukemia cells and in Csnk1a1(−/−) bone marrow cells. Furthermore, we demonstrated that p53(−/−) leukemia cells are resistant to the proliferative defect induced by Csnk1a1 silencing. We next tested whether D4476, a small molecule casein kinase inhibitor, would exhibit selective anti-leukemic effects. Whereas treatment of LSCs with D4476 inhibited their proliferation (IC50: 7μM), concentrations up to 40μM had minimal effects on normal HSPCs. Confirming the specificity of the compound, we found that cells carrying Csnk1a1 shRNAs were sensitized to D4476 in a dose dependent manner. In contrast, overexpression of Csnk1a1 desensitized leukemia cells for D4476 treatment, suggesting that D4476 kills leukemia cells in a Csnk1a1 dependent manner. Finally, we mixed 10,000 HSPCs with 10,000 LSCs and treated them ex vivo with either D4476 or DMSO control for 48 hours followed by injection into lethally irradiated mice. Whereas exposure to the drug caused prolonged latency of disease with some recipients never developing leukemia, there was no significant effect on HSPC donor cell chimerism at 8 weeks post transplantation compared control, indicating limited toxicity from the drug. In summary, these findings identify Csnk1a1 as critical for maintaining both normal HSCs and LSCs via modulation of p53 activity. Importantly, LSCs were significantly more sensitive to small molecule inhibition of Csnk1a1, suggesting that Csnk1a1 may be an attractive new drug target in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Correction: miR-199a-3p knockdown inhibits dedifferentiated liposarcoma (DDLPS) cell viability and enhances apoptosis through targeting casein kinase-1 alpha (CK1α)

RSC Advances ◽  
2019 ◽  
Vol 9 (56) ◽  
pp. 32781-32781
Author(s):  
Ye Cao ◽  
Jiajia Zheng ◽  
Chentao Lv
Keyword(s):  
Cell Viability ◽  
Casein Kinase ◽  
Dedifferentiated Liposarcoma ◽  
Casein Kinase 1 ◽  
Casein Kinase 1 Alpha

Correction for ‘miR-199a-3p knockdown inhibits dedifferentiated liposarcoma (DDLPS) cell viability and enhances apoptosis through targeting casein kinase-1 alpha (CK1α)’ by Ye Cao et al., RSC Adv., 2019, 9, 22755–22763.

scholarly journals Regulation of p53-MDMX Interaction by Casein Kinase 1 Alpha

2005 ◽  
Vol 25 (15) ◽  
pp. 6509-6520 ◽  
Author(s):  
Lihong Chen ◽  
Changgong Li ◽  
Yu Pan ◽  
Jiandong Chen
Keyword(s):  
Dna Damage ◽  
Central Region ◽  
Small Interfering Rna ◽  
Binding Protein ◽  
Casein Kinase ◽  
Ionizing Irradiation ◽  
Mouse Development ◽  
Casein Kinase 1 ◽  
Casein Kinase 1 Alpha ◽  
Interfering Rna

ABSTRACT MDMX is a homolog of MDM2 that is critical for regulating p53 function during mouse development. MDMX degradation is regulated by MDM2-mediated ubiquitination. Whether there are other mechanisms of MDMX regulation is largely unknown. We found that MDMX binds to the casein kinase 1 alpha isoform (CK1α) and is phosphorylated by CK1α. Expression of CK1α stimulates the ability of MDMX to bind to p53 and inhibit p53 transcriptional function. Regulation of MDMX-p53 interaction requires CK1α binding to the central region of MDMX and phosphorylation of MDMX on serine 289. Inhibition of CK1α expression by isoform-specific small interfering RNA (siRNA) activates p53 and further enhances p53 activity after ionizing irradiation. CK1α siRNA also cooperates with DNA damage to induce apoptosis. These results suggest that CK1α is a functionally relevant MDMX-binding protein and plays an important role in regulating p53 activity in the absence or presence of stress.

scholarly journals Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

2021 ◽  
Vol 69 (1) ◽  
Author(s):  
Morvarid Siri ◽  
Hamid Behrouj ◽  
Sanaz Dastghaib ◽  
Mozhdeh Zamani ◽  
Wirginia Likus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chemotherapy Resistance ◽  
Casein Kinase ◽  
Autophagy Flux ◽  
Casein Kinase 1 ◽  
Colorectal Cancer Cells ◽  
High Level ◽  
Casein Kinase 1 Alpha ◽  
Hct116 Cells

AbstractAdjuvant chemotherapy with 5-fluorouracil (5-FU) does not improve survival of patients suffering from a form of colorectal cancer (CRC) characterized by high level of microsatellite instability (MSI-H). Given the importance of autophagy and multi-drug-resistant (MDR) proteins in chemotherapy resistance, as well as the role of casein kinase 1-alpha (CK1α) in the regulation of autophagy, we tested the combined effect of 5-FU and CK1α inhibitor (D4476) on HCT116 cells as a model of MSI-H colorectal cancer. To achieve this goal, the gene expression of Beclin1 and MDR genes, ABCG2 and ABCC3 were analyzed using quantitative real-time polymerase chain reaction. We used immunoblotting to measure autophagy flux (LC3, p62) and flow cytometry to detect apoptosis. Our findings showed that combination treatment with 5-FU and D4476 inhibited autophagy flux. Moreover, 5-FU and D4476 combination therapy induced G2, S and G1 phase arrests and it depleted mRNA of both cell proliferation-related genes and MDR-related genes (ABCG2, cyclin D1 and c-myc). Hence, our data indicates that targeting of CK1α may increase the sensitivity of HCT116 cells to 5-FU. To our knowledge, this is the first description of sensitization of CRC cells to 5-FU chemotherapy by CK1α inhibitor. Graphic abstract

Effect of casein kinase 1α inhibition on autophagy flux and the AKT/phospho-β-catenin (S552) axis in HCT116, a RAS-mutated colorectal cancer cell line

2021 ◽  
pp. 1-10
Author(s):  
Hamid Behrouj ◽  
Atefeh Seghatoleslam ◽  
Pooneh Mokarram ◽  
Saeid Ghavami
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Cell Line ◽  
Casein Kinase ◽  
Colorectal Cancer Cell Line ◽  
Autophagy Flux ◽  
Casein Kinase 1 ◽  
Induced Apoptosis ◽  
Casein Kinase 1 Alpha

The Wnt/β-catenin pathway, which interferes with cell proliferation, differentiation, and autophagy, is commonly dysregulated in colorectal cancer (CRC). Mutation of the RAS oncogene is the most prevalent genetic alteration in CRC and has been linked to activation of protein kinase B (AKT) signaling. Phosphorylation of β-catenin at Ser 552 by AKT contributes to β-catenin stability, transcriptional activity, and increase of cell proliferation. Casein kinase 1 alpha (CK1α) is an enzyme that simultaneously regulates Wnt/β-catenin and AKT. The link of the AKT and Wnt pathway to autophagy in RAS-mutated CRC cells has not well identified. Therefore, we investigated how pharmacological CK1α inhibition (D4476) is involved in regulation of autophagy, Wnt/β-catenin, and AKT pathways in RAS-mutated CRC cell lines. qRT-PCR and immunoblotting experiments revealed that phospho-AKT (S473) and phospho-β-catenin (S552) are constitutively increased in RAS-mutated CRC cell lines, in parallel with augmented CK1α expression. The results also showed that D4476 significantly reduced the AKT/phospho-β-catenin (S552) axis concomitantly with autophagy flux inhibition in RAS-mutated CRC cells. Furthermore, D4476 significantly induced apoptosis in RAS-mutated CRC cells. In conclusion, our results indicate that CK1α inhibition reduces autophagy flux and promotes apoptosis by interfering with the AKT/phospho-β-catenin (S552) axis in RAS-mutated CRC cells.

scholarly journals miR-199a-3p knockdown inhibits dedifferentiated liposarcoma (DDLPS) cell viability and enhances apoptosis through targeting casein kinase-1 alpha (CK1α)

RSC Advances ◽  
2019 ◽  
Vol 9 (39) ◽  
pp. 22755-22763
Author(s):  
Ye Cao ◽  
Jiajia Zheng ◽  
Chentao Lv
Keyword(s):  
Cell Viability ◽  
High Mortality ◽  
Casein Kinase ◽  
Dedifferentiated Liposarcoma ◽  
Casein Kinase 1 ◽  
Aggressive Tumor ◽  
Casein Kinase 1 Alpha

Dedifferentiated liposarcoma (DDLPS) is an aggressive tumor with high mortality.

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