Abstract:The cell division cycle 25A (CDC25A) phosphatase is a key regulator of cell cycle progression that acts on the phosphorylation status of Cyclin–Cyclin-dependent kinase complexes, with an emergent role in the DNA damage response and cell survival control. The regulation of CDC25A activity and its protein level is essential to control the cell cycle and maintain genomic integrity. Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylati… Show more
“…9 ). Given the working venue model that nucleus CDC25A functions in cell cycle progression while cytoplasmic CDC25A is prone to degradation [ 28 , 29 ], we envision that CDC25A exon 6 skipping generated from SRSF10 not only restrains UPS-dependent protein degradation due to the absence of two ubiquitin sites but also accelerates its nuclear aggravation to enhance its cell cycle phosphatase activity. Fig.…”
Background
Alternative splicing (AS) events are extensively involved in the progression of diverse tumors, but how serine/arginine-rich splicing Factor 10 (SRSF10) behaves in hepatocellular carcinoma (HCC) has not been sufficiently studied. We aimed to determine SRSF10 associated AS mechanisms and their effects on HCC progression.
Methods
The expression of SRSF10 in HCC tissues was examined, and the in vitro and in vivo functions of SRSF10 were investigated. The downstream AS targets were screened using RNA sequencing. The interaction between SRSF10 protein and exclusion of cell division cycle 25 A (CDC25A) mRNA was identified using RNA immunoprecipitation and crosslinking immunoprecipitation q-PCR. The effects of SRSF10 on CDC25A posttranslational modification, subcellular distribution, and protein stability were verified through coimmunoprecipitation, immunofluorescence, and western blotting.
Results
SRSF10 was enriched in HCC tissues and facilitated HCC proliferation, cell cycle, and invasion. RNA sequencing showed that SRSF10 promotes exon 6 exclusion of CDC25A pre-mRNA splicing. As a crucial cell cycle mediator, the exon-skipped isoform CDC25A(△E6) was identified to be stabilized and retained in the nucleus due to the deletion of two ubiquitination (Lys150, Lys169) sites in exon 6. The stabilized isoform CDC25A(△E6) derived from AS had stronger cell cycle effects on HCC tumorigenesis, and playing a more significant role than the commonly expressed longer variant CDC25A(L). Interestingly, SRSF10 activated the carcinogenesis role of CDC25A through Ser178 dephosphorylation to cause nuclear retention. Moreover, CDC25A(△E6) was verified to be indispensable for SRSF10 to promote HCC development in vitro and in vivo.
Conclusions
We reveal a regulatory pattern whereby SRSF10 contributes to a large proportion of stabilized CDC25A(△E6) production, which is indispensable for SRSF10 to promote HCC development. Our findings uncover AS mechanisms such as CDC25A that might serve as potential therapeutic targets to treat HCC.
“…9 ). Given the working venue model that nucleus CDC25A functions in cell cycle progression while cytoplasmic CDC25A is prone to degradation [ 28 , 29 ], we envision that CDC25A exon 6 skipping generated from SRSF10 not only restrains UPS-dependent protein degradation due to the absence of two ubiquitin sites but also accelerates its nuclear aggravation to enhance its cell cycle phosphatase activity. Fig.…”
Background
Alternative splicing (AS) events are extensively involved in the progression of diverse tumors, but how serine/arginine-rich splicing Factor 10 (SRSF10) behaves in hepatocellular carcinoma (HCC) has not been sufficiently studied. We aimed to determine SRSF10 associated AS mechanisms and their effects on HCC progression.
Methods
The expression of SRSF10 in HCC tissues was examined, and the in vitro and in vivo functions of SRSF10 were investigated. The downstream AS targets were screened using RNA sequencing. The interaction between SRSF10 protein and exclusion of cell division cycle 25 A (CDC25A) mRNA was identified using RNA immunoprecipitation and crosslinking immunoprecipitation q-PCR. The effects of SRSF10 on CDC25A posttranslational modification, subcellular distribution, and protein stability were verified through coimmunoprecipitation, immunofluorescence, and western blotting.
Results
SRSF10 was enriched in HCC tissues and facilitated HCC proliferation, cell cycle, and invasion. RNA sequencing showed that SRSF10 promotes exon 6 exclusion of CDC25A pre-mRNA splicing. As a crucial cell cycle mediator, the exon-skipped isoform CDC25A(△E6) was identified to be stabilized and retained in the nucleus due to the deletion of two ubiquitination (Lys150, Lys169) sites in exon 6. The stabilized isoform CDC25A(△E6) derived from AS had stronger cell cycle effects on HCC tumorigenesis, and playing a more significant role than the commonly expressed longer variant CDC25A(L). Interestingly, SRSF10 activated the carcinogenesis role of CDC25A through Ser178 dephosphorylation to cause nuclear retention. Moreover, CDC25A(△E6) was verified to be indispensable for SRSF10 to promote HCC development in vitro and in vivo.
Conclusions
We reveal a regulatory pattern whereby SRSF10 contributes to a large proportion of stabilized CDC25A(△E6) production, which is indispensable for SRSF10 to promote HCC development. Our findings uncover AS mechanisms such as CDC25A that might serve as potential therapeutic targets to treat HCC.
“…TRIM33 and BACH1 could regulate the activation of activation of Wnt/β-catenin ( Jiang et al, 2015 ; Li et al, 2022 ), and L. reuteri protect the intestinal mucosal barrier integrity by moderately modulating the Wnt/β-catenin pathway to avoid overactivation ( Wu et al, 2020 ). DYRK2 , RORA and other genes are also involved in the regulation of cell cycle ( Lara-Chica et al, 2022 ), apoptosis ( Li et al, 2022 ) and other activities. The above studies also fully confirmed that these candidate genes identified in this study may be potential regulatory molecules of L. reuteri to protect host cells against E. coli F18ac.…”
Escherichia coli is the main cause of postweaning diarrhea in pigs, leading to economic loss. As a probiotic, Lactobacillus reuteri has been used to inhibit E. coli in clinical applications; however, its integrative interactions with hosts remain unclear, especially in pigs. Here, we found that L. reuteri effectively inhibited E. coli F18ac adhering to porcine IPEC-J2 cells, and explored the genome-wide transcription and chromatin accessibility landscapes of IPEC-J2 cells by RNA-seq and ATAC-seq. The results showed that some key signal transduction pathways, such as PI3K-AKT and MAPK signaling pathways, were enriched in the differentially expressed genes (DEGs) between E. coli F18ac treatment with and without L. reuteri groups. However, we found less overlap between RNA-seq and ATAC-seq datasets; we speculated that this might be caused by histones modification through ChIP-qPCR detection. Furthermore, we identified the regulation of the actin cytoskeleton pathway and a number of candidate genes (ARHGEF12, EGFR, and DIAPH3) that might be associated with the inhibition of E. coli F18ac adherence to IPEC-J2 cells by L. reuteri. In conclusion, we provide a valuable dataset that can be used to seek potential porcine molecular markers of E. coli F18ac pathogenesis and L. reuteri antibacterial activity, and to guide the antibacterial application of L. reuteri.
“…In addition, CDC25A is a key factor in regulating the cell cycle and is regulated by eca-miR-200a. Mutual feedback regulation between CDC25A and DYRK2 has important implications for genotoxic stress pathways, apoptosis and cell cycle regulation [ 43 ]. In epididymal tissue, four genes were demonstrated with miRNA roles, including BMP5 , GCNT1 , FGF7 and THSD4 .…”
Donkeys, with high economic value for meat, skin and milk production, are important livestock. However, the current insights into reproduction of donkeys are far from enough. To obtain a deeper understanding, the differential expression analysis and weighted gene co-expression network analysis (WGCNA) of transcriptomic data of testicular and epididymis tissues in donkeys were performed. In the result, there were 4313 differentially expressed genes (DEGs) in the two tissues, including 2047 enriched in testicular tissue and 2266 in epididymis tissue. WGCNA identified 1081 hub genes associated with testis development and 6110 genes with epididymal development. Next, the tissue-specific genes were identified with the above two methods, and the gene ontology (GO) analysis revealed that the epididymal-specific genes were associated with gonad development. On the other hand, the testis-specific genes were involved in the formation of sperm flagella, meiosis period, ciliary assembly, ciliary movement, etc. In addition, we found that eca-Mir-711 and eca-Mir-143 likely participated in regulating the development of epididymal tissue. Meanwhile, eca-Mir-429, eca-Mir-761, eca-Mir-200a, eca-Mir-191 and eca-Mir-200b potentially played an important role in regulating the development of testicular tissue. In short, these results will contribute to functional studies of the male reproductive trait in donkeys.
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