PolyC-binding proteins enhance expression of the CDK2 cell cycle regulatory protein via alternative splicing

Ji, Xinjun; Humenik, Jesse; Yang, Daphne; Liebhaber, Stephen A.

doi:10.1093/nar/gkx1255

Cited by 20 publications

(13 citation statements)

References 63 publications

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“…Phosphorylated CDC6 translocates to the cytoplasm to prevent re-replication of the DNA [57] (Figure 1). Regulation of CDK2 alternative splicing by exclusion of exon 5 represses CDK2 protein expression and thus impacts cell cycle control [58]. The regulation of CDK2 alternative splicing is coordinated by poly(rC) binding protein 1 and 2 (PCBP1/2) as well as the splicing factor PTB.…”

Section: Cdc-like Kinase 1 (Clk1)mentioning

confidence: 99%

Splicing to Keep Cycling: The Importance of Pre-mRNA Splicing during the Cell Cycle

et al. 2021

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Pre-mRNA splicing is a fundamental process in mammalian gene expression and alternative splicing plays an extensive role in generating protein diversity. Since the majority of genes undergo pre-mRNA splicing, most cellular processes depend on proper spliceosome function.Here we focus on the cell cycle and describe its dependence on pre-mRNA splicing and accurate alternative splicing. We outline the key cell cycle factors and their known alternative splicing isoforms. We discuss different levels of pre-mRNA splicing regulation such as posttranslational modifications and changes in expression of splicing factors. We describe the effect of chromatin dynamics on pre-mRNA splicing during the cell cycle. In addition, we focus on the spliceosome component SF3B1, which is mutated in many types of cancer, and describe the link of SF3B1 and its inhibitors to cell cycle.

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Section: Cdc-like Kinase 1 (Clk1)mentioning

confidence: 99%

Splicing to Keep Cycling: The Importance of Pre-mRNA Splicing during the Cell Cycle

et al. 2021

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“…CDK2 and cyclin E1 have been regarded to be cell cycle regulators in malignant tumors. [30][31][32][33] Moreover, Liu et al found that NF-κB induced cell cycle arrest in laryngeal squamous cell cancer via downregulation of CDK2. 34 Overexpression of p38γ could promote the progression of human colorectal cancer via upregulation of cyclin E1.…”

Section: Dovepressmentioning

confidence: 99%

<p>Downregulation of miR-575 Inhibits the Tumorigenesis of Gallbladder Cancer via Targeting p27 Kip1</p>

Qin

Huang

et al. 2020

OTT

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Background: Gallbladder cancer (GBC) is the most common biliary tract malignant cancer worldwide. It has been reported that microRNA-575 (miR-575) was involved in the tumorigenesis of many cancers. However, the role of miR-575 during the progression of GBC remains largely unknown. Methods: The expression of miR-575 in GBC cells was detected by quantitative real-time polymerase chain reaction. The proliferation of GBC cells was examined by CCK-8 assay and Ki-67 staining. Apoptosis of GBC cells was measured by flow cytometry, and cell invasion was tested by transwell assay. Moreover, protein expressions in GBC cells were evaluated using Western blot. The target gene of miR-575 was predicted using Targetscan and miRDB. Finally, xenograft tumor model was established to verify the function of miR-575 in GBC in vivo. Results: Our findings indicated that miR-575 antagonist decreased the proliferation and invasion of GBC cells. In addition, miR-575 antagonist significantly induced apoptosis of GBC cells via inducing G1 arrest. Meanwhile, p27 Kip1 was found to be a direct target of miR-575 with luciferase reporter assay. Moreover, miR-575 antagonist significantly decreased the expressions of CDK1 and cyclin E1 and upregulated the levels of cleaved caspase3 and p27 Kip1 in GBC cells. Finally, miR-575 antagonist notably suppressed GBC tumor growth in vivo. Conclusion: Downregulation of miR-575 significantly inhibited the tumorigenesis of GBC via targeting p27 Kip1. Thus, miR-575 might be a potential novel target for the treatment of GBC.

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“…Previously, it has been demonstrated that RNA splicing and cell cycle are interconnected. Adequate splicing of cell cycle genes, such as CDC25 and CDK2, are required for a proper transition between different cell cycle phases 49,50 and disruption of core spliceosome components, such as deletion of SRSF2, leads to G2-phase cell cycle arrest and apoptosis [51][52][53] . It is possible that mutant splicing factors diminish the capacity of the spliceosome, which is critical for normal cell cycle progression, and that mutant cells heavily rely on the remaining wildtype allele for survival.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screening identifies cell-cycle control as a synthetic lethal pathway with SRSF2P95H mutation

Chalk

Nikolić

et al. 2022

Blood Advances

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Current strategies to target RNA splicing mutant myeloid cancers proposes targeting the remaining splicing apparatus. This approach has only been modestly sensitizing and is also toxic to non-mutant bearing wild-type cells. To explore potentially exploitable genetic interactions with spliceosome mutations, we combined data mining and functional screening for synthetic lethal interactions with an Srsf2P95H/+ mutation. Analysis of mis-splicing events in a series of both human and murine SRSF2P95H mutant samples across multiple myeloid diseases (AML, MDS, CMML) was performed to identify conserved mis-splicing events. From this analysis, we identified that the cell cycle and DNA repair pathways were overrepresented within the conserved mis-spliced transcript sets. In parallel, to functionally define pathways essential for survival and proliferation of Srsf2P95H/+ cells, we performed a genome-wide CRISPR loss of function screen using Hoxb8 immortalized R26-CreERki/+ Srsf2P95H/+ and R26-CreERki/+ Srsf2+/+ cell lines. We assessed loss of sgRNA representation at three timepoints: immediately after Srsf2P95H/+ activation, and at one week and two weeks post Srsf2P95H/+ mutation. Pathway analysis demonstrated that the cell cycle and DNA damage response pathways were amongst the top synthetic lethal pathways with Srsf2P95H/+ mutation. Based on the loss of guide RNAs targeting Cdk6, we identified that Palbociclib, a CDK6 inhibitor, showed preferential sensitivity in Srsf2P95H/+ cell lines and in primary non-immortalized lin-cKIT+Sca-1+ cells compared to wild type controls. Our data strongly suggest that the cell cycle and DNA damage response pathways are required for Srsf2P95H/+ cell survival, and that Palbociclib could be an alternative therapeutic option for targeting SRSF2 mutant cancers.

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PolyC-binding proteins enhance expression of the CDK2 cell cycle regulatory protein via alternative splicing

Cited by 20 publications

References 63 publications

Splicing to Keep Cycling: The Importance of Pre-mRNA Splicing during the Cell Cycle

Splicing to Keep Cycling: The Importance of Pre-mRNA Splicing during the Cell Cycle

<p>Downregulation of miR-575 Inhibits the Tumorigenesis of Gallbladder Cancer via Targeting p27 Kip1</p>

Genome-wide screening identifies cell-cycle control as a synthetic lethal pathway with SRSF2P95H mutation

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