WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

Expression and clinical correlation of casein kinase 1γ2 in head and neck squamous cell carcinoma / 国际生物医学工程杂志

Objective:To explore the role of casein kinase 1 gamma 2 (CSNK1G2) in the development and progression of head and neck squamous cell carcinoma (HNSC).Methods:Based on the Cancer Genome Atlas (TCGA), LinkedOmics and UALCAN were used to analyze the relationship among the mRNA expression of CSNK1G2, methylation, copy number variation and clinical indicators in HNSC, as well as to analysis CSNK1G2 related co-expression genes and proteins. The expression of CSNK1G2 in HNSC was verified by RT-qPCR experiments of clinical samples. Protein interaction network analysis on CSNK1G2 expression-related proteins was performed using STRING database.Results:UALCAN analysis showed that the expression of CSNK1G2 mRNA in HNSC was higher than that in normal tissues ( P<0.001), and the expression of CSNK1G2 mRNA was up-regulated in lower differentiation and Human Papilloma Virus (HPV)-positive HNSC (all P<0.05). But in HNSC with different pathological stages, different age stages and different lymph node metastasis stages (N stage), there was no difference in the amount of CSNK1G2 mRNA expression (all P>0.05). The RT-qPCR experiment confirmed the increased expression of CSNK1G2 mRNA in HNSC. LinkedOmincs analysis results showed that CSNK1G2 mRNA expression was positively correlated with CSNK1G2 copy number variation ( P<0.001) and negatively correlated with methylation ( P<0.001). Survival analysis results showed that high CSNK1G2 mRNA expression and copy number mutations predicted better survival ( P=0.033, P=0.015), while methylation levels were not associated with survival ( P=0.458). Gene set enrichment analysis results showed that CSNK1G2-related co-expression genes were mainly in DNA replication. The STRING's protein interaction network analysis results showed that TP53, CHEK1, and CHEK2 may be key proteins. These proteins are significantly associated with high expression levels of CSNK1G2. Conclusions:CSNK1G2 may cooperate with TP53, CHEK1 and CHEK2 related proteins to promote the development of HNSC and tumor proliferation, but does not affect the metastasis and spread of HNSC. An increase in the expression of CSNK1G2 in HNSC may indicate a better survival prognosis.

Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators

RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an 'undruggable' feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.

Research progress of regulation mechanism of MDMX and CK1αin p53 tumor suppressor protein / 天津医药

As a tumor suppressor, p53 is activated by numerous cellular and environmental signals, and plays a criticalrole in the cell cycle regulation, cell apoptosis and senenscence. The murine double minute (MDM)2 and double minute mu?rine 4 (MDMX) are two important regulators. MDMX is a p53 binding protein with strong sequence homology to MDM2, but lacks ubiquitin ligase activity, and which is unable to target p53 for proteasomal degradation. MDMX regulates p53 activity through its binding with p53 and its postranscriptional modification. MDMX in the closed and open structure binds to p53 to regulate its activity. As the main partner of MDMX, casein kinase 1 alpha (CK1α) disrupts the intramolecular binding in MD?MX in the cooperation to regulate p53 activity. The process of MDMX and CK1αin the regulation of p53 is multi-step and complicated. In this paper the mechanism of MDMX and CK1αin the regulation of p53 protein was reviewed.

The CK1 gene family: expression patterning in zebrafish development

Protein kinase CK1 is a ser/thr protein kinase family which has been identified in the cytosol cell fraction, associated with membranes as well as in the nucleus. Several isoforms of this gene family have been described in various organisms: CK1 , CK1á, CK1δ, CK1å and CK1γ. Over the last decade, several members of this family have been involved in development processes related to wnt and sonic hedgehog signalling pathways. However, there is no detailed temporal information on the CK1 family in embryonic stages, even though orthologous genes have been described in several different vertebrate species. In this study, we describe for the first time the cloning and detailed expression pattern of five CK1 zebrafish genes. Sequence analysis revealed that zebrafish CK1 proteins are highly homologous to other vertebrate orthologues. Zebrafish CK1 genes are expressed throughout development in common and different territories. All the genes studied in development show maternal and zygotic expression with the exception of CK1å. This last gene presents only a zygotic component of expression. In early stages of development CK1 genes are ubiquitously expressed with the exception of CK1å. In later stages the five CK1 genes are expressed in the brain but not in the same way. This observation probably implicates the CK1 family genes in different and also in redundant functions. This is the first time that a detailed comparison of the expression of CK1 family genes is directly assessed in a vertebrate system throughout development.

Association Study on Simple Febrile Seizures and Casein Kinase 1,Gamma 1 Gene / 实用儿科临床杂志

0.05).Conclusion CSNK1G1 gene may not be a susceptibility gene for sFS in the northern Chinese Han population.