Maternal Embryonic Leucine Zipper Kinase (MELK):  A Novel Regulator in Cell Cycle Control, Embryonic Development, and Cancer

Jiang, Pengfei; Zhang, Deli

doi:10.3390/ijms141121551

Cited by 71 publications

(74 citation statements)

References 56 publications

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“…To confirm these subtle differences, we selected a dozen targets for experimental validation, based mainly on their potential relevance to disease (Discussion and Table 1) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). We examined these splicing events by 32 P RT-PCR using total RNA extracted from all eight CRISPR cell lines and from K562 parental cells.…”

Section: Resultsmentioning

confidence: 99%

Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities

Zhang

Lieu

Ali

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

180

197

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Serine/arginine-rich splicing factor 2 (SRSF2) is an RNA-binding protein that plays important roles in splicing of mRNA precursors. SRSF2 mutations are frequently found in patients with myelodysplastic syndromes and certain leukemias, but how these mutations affect SRSF2 function has only begun to be examined. We used clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein-9 nuclease to introduce the P95H mutation to SRSF2 in K562 leukemia cells, generating an isogenic model so that splicing alterations can be attributed solely to mutant SRSF2. We found that SRSF2 (P95H) misregulates 548 splicing events (<1% of total). Of these events, 374 involved the inclusion of cassette exons, and the inclusion was either increased (206) or decreased (168). We detected a specific motif (UCCA/UG) enriched in the more-included exons and a distinct motif (UGGA/UG) in the moreexcluded exons. RNA gel shift assays showed that a mutant SRSF2 derivative bound more tightly than its wild-type counterpart to RNA sites containing UCCAG but bound less tightly to UGGAG sites. Thus in most cases the pattern of exon inclusion or exclusion correlated with stronger or weaker RNA binding, respectively. We further show that the P95H mutation does not affect other functions of SRSF2, i.e., protein-protein interactions with key splicing factors. Our results thus demonstrate that the P95H mutation positively or negatively alters the binding affinity of SRSF2 for cognate RNA sites in target transcripts, leading to misregulation of exon inclusion. Our findings shed light on the mechanism of the disease-associated SRSF2 mutation in splicing regulation and also reveal a group of misspliced mRNA isoforms for potential therapeutic targeting.spliceosome | pre-mRNA splicing | serine/arginine-rich proteins | myelodysplastic syndromes | leukemia M yelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective production of myeloid blood cells, which have various risks of progression into acute myeloid leukemia (AML) (1, 2). The most frequently occurring mutations found in patients with MDS involve genes encoding pre-mRNA splicing factors, including Splicing factor 3B, subunit 1 (SF3B1), Serine/argininerich splicing factor 2 (SRSF2), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 (ZRSR2) (3-6), suggesting that altered RNA splicing may play a critical role in the pathogenesis of MDS. Despite some recent advances (e.g., ref. 7; see Discussion), the molecular mechanisms by which the mutated splicing factors misregulate pre-mRNA splicing have not been studied thoroughly. However, it is now well established that splicing deregulation contributes to multiple diseases, especially cancer (8, 9).SRSF2 is a well-studied serine/arginine-rich splicing factor (SR protein). SR proteins play important roles in the regulation of both constitutive and alternative pre-mRNA splicing, functioning, for ...

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Section: Resultsmentioning

confidence: 99%

Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities

Zhang

Lieu

Ali

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

180

197

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“…Previous studies have indicated their roles in lung cancer (24), colorectal cancer (25) and oral cancer (26). MELK, which is a highly conserved serine/threonine kinase, is a regulator in cell cycle control and cancer (27,28). Dysregulated expression of MELK is associated with a poor prognosis in breast cancer (29).…”

Section: Discussionmentioning

confidence: 99%

Identification of prognostic genes in kidney renal clear cell carcinoma by RNA-seq data analysis

et al. 2017

Molecular Medicine Reports

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The present study aimed to analyze RNA-seq data of kidney renal clear cell carcinoma (KIRC) to identify prognostic genes. RNA-seq data were downloaded from The Cancer Genome Atlas. Feature genes with a coefficient of variation (CV) >0.5 were selected using the genefilter package in R. Gene co-expression networks were constructed with the WGCNA package. Cox regression analysis was performed using the survive package. Furthermore, a functional enrichment analysis was conducted using Database for Annotation, Visualization and Integrated Discovery tools. A total of 533 KIRC samples were collected, from which 6,758 feature genes with a CV >0.5 were obtained for further analysis. The KIRC samples were divided into two sets: The training set (n=319 samples) and the validation set (n=214 samples). Subsequently, gene co-expression networks were constructed for the two sets. A total of 12 modules were identified, and the green module was significantly associated with survival time. Genes from the green module were revealed to be implicated in the cell cycle and p53 signaling pathway. In addition, a total of 11 hub genes were revealed, and 10 of them (CCNA2, CDC20, CDCA8, GTSE1, KIF23, KIF2C, KIF4A, MELK, TOP2A and TPX2) were validated as possessing prognostic value, as determined by conducting a survival analysis on another gene expression dataset. In conclusion, a total of 10 prognostic genes were identified in KIRC. These findings may help to advance the understanding of this disease, and may also provide potential biomarkers for therapeutic development.

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“…Maternal embryonic leucine zipper kinase (MELK) is a kind of cell cycle dependent conserved serine/threonine protein kinase, at chromosome 9p13.2. Unlike other members of the family, MELK is not related to cellular energy metabolism balance . MELK is highly expressed in a wide range of malignant tumors, including hepatocellular carcinoma, breast cancer, melanoma, acute leukemia, ovarian cancer, neuroblastoma and myeloma .…”

Section: Introductionmentioning

confidence: 99%

“…MELK is highly expressed in a wide range of malignant tumors, including hepatocellular carcinoma, breast cancer, melanoma, acute leukemia, ovarian cancer, neuroblastoma and myeloma . It is actively involved in cell cycle regulation, proliferation, apoptosis, and tumor formation , . However, the role of MELK in cervical cancer has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer

Wang

Shen

et al. 2018

Cancer Medicine

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Maternal embryo leucine zipper kinase (MELK) is highly expressed in a variety of malignant tumors and involved in cell cycle regulation, cell proliferation, apoptosis, tumor formation etc However, the biological effects of MELK in cervical cancer are still uninvestigated. This study aimed to explore the expression of MELK in cervical cancer, as well as its effects on the proliferation, apoptosis, DNA damage repair on cervical cancer cell line in vitro and to provide novel ideas for further improving the clinical efficacy of cervical cancer. Immunohistochemistry, Western blot, RT‐qPCR, CCK8, and immunofluorescence techniques were used to detect the expression of MELK in cervical cancer tissues, paracancerous tissues, and cervical cancer cell lines. Several cervical cancer cell lines were treated with MELK knockdown by siRNA and MELK selective inhibitor OTSSP167. The effects on proliferation, apoptosis, and colony formation capacity, and tumor cell DNA damage repair‐related factor were detected in cell lines. Our data showed that the high expression rate of MELK in cervical cancer patients was 56.92%. MELK expression in cervical cancer samples was significantly higher than that in paraneoplastic tissues. Highly expressed MELK correlated with the cervical histopathological grading and greatly increased with the cervical histopathological grading, from normal cervix and cervical intraepithelial neoplasia to cervical cancer. Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage. The knockdown of MELK with siRNA and OTSSP167 had strong inhibition effects on the proliferation, apoptosis, and colony formation of cervical cancer cells. MELK knockdown could also aggravate the DNA damage of cervical cancer cells possibly by homologous recombination repair pathway. Therefore, MELK may be a predicting marker of poor prognosis of cervical cancer and may also be a new therapeutic target for cervical cancer, providing ideas for improving the therapeutic effect of cervical cancer.

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Maternal Embryonic Leucine Zipper Kinase (MELK): A Novel Regulator in Cell Cycle Control, Embryonic Development, and Cancer

Cited by 71 publications

References 56 publications

Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities

Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities

Identification of prognostic genes in kidney renal clear cell carcinoma by RNA-seq data analysis

Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer

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