Abstract
Aberrant profiles of pre-mRNA splicing are frequently observed in cancer. At the molecular level, an altered profile results from a complex interplay between chromatin modifications, the transcriptional elongation rate of RNA polymerase, and effective binding of the spliceosome to the generated transcripts. Key players in this interplay are regulatory splicing factors (SFs) that bind to gene-specific splice-regulatory sequence elements. Although mutations in genes of some SFs were described, a major driver of aberrant splicing profiles is oncogenic signal transduction pathways. Signaling can affect either the transcriptional expression levels of SFs or the post-translational modification of SF proteins, and both modulate the ratio of nuclear versus cytoplasmic SFs in a given cell. Here, we will review currently known mechanisms by which cancer cell signaling, including the mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 (PI3)-kinase pathway (PI3K) and wingless (Wnt) pathways but also signals from the tumor microenvironment, modulate the activity or subcellular localization of the Ser/Arg rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) families of SFs.
Highlights
Transcription of a protein-coding gene in human cells generates a primary transcript, the pre-mRNA that still contains intervening intronic sequences, which in general are co-transcriptionally removed during the process of mRNA splicing
In contrast to genetic diseases, where a disease-causing gene can suffer a mutation that interferes with the normal splicing process of its mRNA, aberrant profiles observed in tumors mostly reflect the selection of endogenous alternative splicing variants with different functional properties that allow the malignant progression of initiated tumor cells
Aberrant profiles observed in tumors mostly reflect the selection of endogenous alternative splicing variants with different functional properties that allow the malignant progression of initiated tumor cells and contribute to tumor progression
Summary
Transcription of a protein-coding gene in human cells generates a primary transcript, the pre-mRNA that still contains intervening intronic sequences, which in general are co-transcriptionally removed during the process of mRNA splicing. The genetic alterations underlying the observed changes in splicing factor expression in tumors remain mostly unclear; recent genome-wide analyses have emphasized the existence of a ‘dark matter’ in cancer genomes that requires better characterization, namely the potential cancer-driving mutations in non-coding regions that may affect gene regulation steps such as transcription, splicing, mRNA stability, or translation [33]. Another mechanism disturbing the balance is the post-translational modification of splicing factor proteins, with consequences for their activity, subcellular localization, or proteasomal degradation. This review will focus on the deregulation of splicing profiles in tumor cells in consequence of either oncogene-driven signaling or signals received from the tumor microenvironment
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