The SR protein family comprises a number of phylogenetically conserved and structurally related proteins with a characteristic domain rich in arginine and serine residues, known as the RS domain. They play significant roles in constitutive pre-mRNA splicing and are also important regulators of alternative splicing. In addition they participate in post-splicing activities, such as mRNA nuclear export, nonsense-mediated mRNA decay and mRNA translation. These wide-ranging roles of SR proteins highlight their importance as pivotal regulators of mRNA metabolism, and if these functions are disrupted, developmental defects or disease may result. Furthermore, animal models have shown a highly specific, non-redundant role for individual SR proteins in the regulation of developmental processes. Here, we will review the current literature to demonstrate how SR proteins are emerging as one of the master regulators of gene expression.
Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.
Pre-mRNA splicing is a predominantly co-transcriptional event which involves a large number of essential splicing factors. Within the mammalian cell nucleus, most splicing factors are concentrated in 20-40 distinct domains called speckles. The function of speckles and the organization of cellular transcription and pre-mRNA splicing in vivo are not well understood. We have investigated the dynamic properties of splicing factors in nuclei of living cells. Here we show that speckles are highly dynamic structures that respond specifically to activation of nearby genes. These dynamic events are dependent on RNA polymerase II transcription, and are sensitive to inhibitors of protein kinases and Ser/Thr phosphatases. When single genes are transcriptionally activated in living cells, splicing factors leave speckles in peripheral extensions and accumulate at the new sites of transcription. We conclude that one function of speckles is to supply splicing factors to active genes. Our observations demonstrate that the interphase nucleus is far more dynamic in nature than previously assumed.
The opposing effects of SF2/ASF and heterogeneous nuclear ribonucleoprotein (hnRNP) A1 influence alternative splicing in vitro. SF2/ASF or hnRNP A1 complementary DNAs were transiently overexpressed in HeLa cells, and the effect on alternative splicing of several cotransfected reporter genes was measured. Increased expression of SF2/ASF activated proximal 5' splice sites, promoted inclusion of a neuron-specific exon, and prevented abnormal exon skipping. Increased expression of hnRNP A1 activated distal 5' splice sites. Therefore, variations in the intracellular levels of antagonistic splicing factors influence different modes of alternative splicing in vivo and may be a natural mechanism for tissue-specific or developmental regulation of gene expression.
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