Aberrant pre-mRNA splicing of a highly conserved cell cycle regulator, CDC25C, in myelodysplastic syndromes.
ABSTRACT Alternative pre-mRNA splicing alters gene expression and protein function, and aberrant splicing patterns can be associated with neoplasia. The potential role of disordered RNA splicing in myelodysplastic syndrome (MDS) is unexplored. We analysed the splicing repertoire of CDC25C- a gene localised to chromosome 5q31 and encoding a cyclin/cyclin-dependent-kinase regulatory phosphatase critical for cell cycle checkpoint control - in MDS, acute myeloid leukemia, chronic lymphocytic leukemia and healthy tissues. Five novel splicing isoforms were detected, and the splicing patterns were generally distinct in neoplastic samples compared with healthy controls. One of the novel isoforms, which we have termed CDC25C-6, occurred in 58% of the samples in our cohort. The results of this study suggest the possibility of aberrant splicing contributing to the phenotype in MDS and other haematologic malignancies.
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ABSTRACT: The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of several human malignancies, including acute myeloid leukemia (AML); and CDC25 inhibition is therefore considered as a possible anticancer strategy. Firstly, upregulation of CDC25A can enhance cell proliferation and the expression seems to be controlled through PI3K-Akt-mTOR signaling, a pathway possibly mediating chemoresistance in human AML. Loss of CDC25A is also important for the cell cycle arrest caused by differentiation induction of malignant hematopoietic cells. Secondly, high CDC25B expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors in primary human AML cells, and inhibition of this isoform seems to reduce AML cell line proliferation through effects on NFκB and p300. Finally, CDC25C seems important for the phenotype of AML cells at least for a subset of patients. Many of the identified CDC25 inhibitors show cross-reactivity among the three CDC25 isoforms. Thus, by using such cross-reactive inhibitors it may become possible to inhibit several molecular events in the regulation of cell cycle progression and even cytoplasmic signaling, including activation of several CDKs, through the use of a single drug. Such combined strategies will probably be an advantage in human cancer treatment.Molecules 11/2014; 19(11):18414-18447. DOI:10.3390/molecules191118414 · 2.10 Impact Factor
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ABSTRACT: The clinicopathologic heterogeneity of myelodysplastic syndromes (MDS) is driven by diverse, somatically acquired genetic abnormalities. Recent technological advances have enabled the identification of many new mutations, which have implicated novel pathways in MDS pathogenesis, including RNA splicing and epigenetic regulation of gene expression. Molecular abnormalities, either somatic point mutations or chromosomal lesions, can be identified in the vast majority of MDS cases and underlie specific disease phenotypes. As the full array of molecular abnormalities is characterized, genetic variables are likely to complement standard morphologic evaluation in future MDS classification schemes and risk models. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 8 is . Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.Annual Review of Pathology Mechanisms of Disease 08/2012; DOI:10.1146/annurev-pathol-011811-132436 · 22.13 Impact Factor
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ABSTRACT: CDC25 phosphatases control cell cycle progression by activating cyclin dependent kinases. The three CDC25 isoforms encoding genes are submitted to alternative splicing events which generate at least two variants for CDC25A and five for both CDC25B and CDC25C. An over-expression of CDC25 was reported in several types of cancer, including breast cancer, and is often associated with a poor prognosis. Nevertheless, most of the previous studies did not address the expression of CDC25 splice variants. Here, we evaluated CDC25 spliced transcripts expression in anti-cancerous drug-sensitive and resistant breast cancer cell lines in order to identify potential breast cancer biomarkers. CDC25 splice variants mRNA levels were evaluated by semi-quantitative RT-PCR and by an original real-time RT-PCR assay. CDC25 spliced transcripts are differentially expressed in the breast cancer cell lines studied. An up-regulation of CDC25A2 variant and an increase of the CDC25C5/C1 ratio are associated to the multidrug-resistance in VCREMS and DOXOR breast cancer cells, compared to their sensitive counterpart cell line MCF-7. Additionally, CDC25B2 transcript is exclusively over-expressed in VCREMS resistant cells and could therefore be involved in the development of certain type of drug resistance. CDC25 splice variants could represent interesting potential breast cancer prognostic biomarkers.Clinical Chemistry and Laboratory Medicine 06/2011; 49(10):1707-14. DOI:10.1515/CCLM.2011.635 · 2.96 Impact Factor