Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Modulates Serine/Arginine-rich Protein 55 (SRp55)-promoted Tau Exon 10 Inclusion

Yin, Xiaomin; Jin, Nana; Gu, Jianlan; Shi, Jing; Zhou, Jianhua; Chen, Gong; Iqbal, Khalid; Grundke‐Iqbal, Inge; Liu, Fei

doi:10.1074/jbc.m112.355412

Cited by 88 publications

(68 citation statements)

References 45 publications

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“…First, we studied the domain-specific role of SRSF6 in CRC. Because SRSF6 contains two RNA recognition motifs at the N terminus and RS domains at the C terminus,22 we generated various deletion mutants of SRSF6 (figure 7A,B). When transfecting these mutants into SW620 cells with SRSF6 shRNA, we found that RRM1 deletion mutant could significantly decrease ZO-1 exon23 inclusion transcript similar to SRSF6 full-length expression vector, but the RRM2 deletion or RRM1&RRM2 deletion mutant failed to inhibit ZO-1 exon23 inclusion (figure 7C).…”

Section: Resultsmentioning

confidence: 99%

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Wan

Shen

et al. 2017

Gut

138

146

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Section: Resultsmentioning

confidence: 99%

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Wan

Shen

et al. 2017

Gut

138

146

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“…The SR splicing factor SRSF6 may regulate the AS of HTT through the binding to the 5′ end of mutant HTT mRNA, suggesting a role for this protein in the generation of these transcript isoforms and in the pathogenesis of HD . SRSF6 also regulates the AS of the microtubule‐associated protein tau ( MAPT ) gene, resulting in increased expression of the 4R/3R (four‐ or three‐microtubule‐binding repeats) tau isoform ratio in neuroblastoma cells . Interestingly, the 4R/3R tau ratio is significantly increased in the cortex of HD patients and confers a gain of toxicity in HD pathogenesis .…”

Section: Connections Between Prp40 Proteins and Human Diseasementioning

confidence: 99%

Prp40 and early events in splice site definition

et al. 2015

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The alternative splicing (AS) of precursor messenger RNA (pre-mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre-mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active-site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre-mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17-32. doi: 10.1002/wrna.1312 For further resources related to this article, please visit the WIREs website.

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“…Upregulation of Dyrk1A, a tau kinase encoded by a gene located on Down syndrome critical region, suppresses tau exon 10 inclusion, resulting in an increased 3R-tau expression. Therefore, overexpression of Dyrk1A in Down syndrome due to increased gene dosage increases 3R-tau expression, and appears to contribute to earlier onset of tau pathology in this disease [57, 106, 118]. …”

Section: Etiopathogenesis Of Neurofibrillary Degenerationmentioning

confidence: 99%

Alzheimer disease therapeutics: Focus on the disease and not just plaques and tangles

Iqbal

Liu

Chen

2014

Biochemical Pharmacology

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The bulk of AD research during the last twenty-five years has been Aβ-centric based on a strong faith in the Amyloid Cascade Hypothesis which is not supported by the data on humans. To date, Aβ-based therapeutic clinical trials on sporadic cases of AD have been negative. Although most likely the major reason for the failure is that Aβ is not an effective therapeutic target for sporadic AD, initiation of the treatment at mild to moderate stages of the disease is blamed as too late to be effective. Clinical trials on presymptomatic familial AD cases have been initiated with the logic that Aβ is a trigger of the disease and hence initiation of the Aβ immunotherapies several years before any clinical symptoms would be effective. There is an urgent need to explore targets other than Aβ. There is now increasing interest in inhibiting tau pathology, which does have a far more compelling rationale than Aβ. AD is multifactorial and over 99% of the cases are the sporadic form of the disease. Understanding of the various etiopathogenic mechanisms of sporadic AD and generation of the disease-relevant animal models are required to develop rational therapeutic targets and therapies. Treatment of AD will require both inhibition of neurodegeneration and regeneration of the brain.

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Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Modulates Serine/Arginine-rich Protein 55 (SRp55)-promoted Tau Exon 10 Inclusion

Cited by 88 publications

References 45 publications

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Prp40 and early events in splice site definition

Alzheimer disease therapeutics: Focus on the disease and not just plaques and tangles

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