STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA

Chen, An Jou; Paik, Ji Hye; Zhang, Hailei; Shukla, Sachet A.; Mortensen, Richard M.; Hu, Jian; Ying, Haoqiang; Hu, Baoli; Hurt, Jessica A.; Farny, Natalie G.; Dong, Caroline C.; Xiao, Yonghong; Wang, Y. Alan; Silver, Pamela A.; Chin, Lynda; Vasudevan, Shobha; DePinho, Ronald A.

doi:10.1101/gad.189001.112

Cited by 107 publications

(106 citation statements)

References 56 publications

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“…Homozygotes of N-ethyl-N-nitrosourea (ENU)-mutagenized or targeted deficient alleles exhibit a deficiency of vasculogenesis in the yolk sac and die at around embryonic day (E)10.5 (Noveroske et al, 2002;Li et al, 2003). Furthermore, a recent report demonstrated that QKI plays an important role in cancer suppression through stabilization of a microRNA (Chen et al, 2012). Thus, QKI appears to have pleiotropic functions in mammalian development.…”

Section: Developmental Genetics Of Mutations Used As Markers For T-hamentioning

confidence: 99%

Developmental genetics of the mouse <i>t</i>-complex

Sugimoto

2014

Genes Genet. Syst.

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The proximal third of mouse chromosome 17 is known as the t-complex. The thaplotype is a variant form of this region containing four tandem inversions compared with the wild-type t-complex, and thus recombination in heterozygotes of the t-haplotype is strongly suppressed along the entire t-complex region. Within this genetically locked t-haplotype, many mutations related to various interesting phenotypes (e.g., taillessness, transmission ratio distortion, recessive lethality) have accumulated, and many mouse geneticists have been attracted to t-haplotype research. Many recessive lethal mutations known as t-complex lethal mutations have been found, and detailed phenotypic analyses have revealed that the functions of t-lethal genes are related to important developmental events. Therefore, identification of the genes responsible for these lethal mutations may contribute to our understanding of the mechanisms of mammalian development. In this review, I introduce the phenotypes of t-lethal mutations and describe recent findings, including our results regarding the molecular identification of a t-lethal gene.

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Section: Developmental Genetics Of Mutations Used As Markers For T-hamentioning

confidence: 99%

Developmental genetics of the mouse <i>t</i>-complex

Sugimoto

2014

Genes Genet. Syst.

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“…It has been found to regulate multiple posttranscriptional processes, including premRNA splicing, mRNA localization, mRNA stability, and protein translation (43)(44)(45)(46)(47)(48)(49)(50). There are three major isoforms of QKI due to AS, QKI-5, QKI-6, and QKI-7 (51,52).…”

Section: Comprehensive Determination Of Changes In As During Emtmentioning

confidence: 99%

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Yang

Park

Bebee

et al. 2016

Molecular and Cellular Biology

133

165

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fThe epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins epithelial splicing regulatory proteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robust in vitro EMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions.A lternative splicing (AS) is a process by which a single gene transcript can be differentially spliced to yield numerous splice variants that can encode different protein isoforms and thereby greatly expand the protein coding capacity of the genome. Nearly all human genes are alternatively spliced, and cell-typespecific protein isoforms have been shown to be functionally essential for cell fate and viability (1-3). This process is under complex regulation by various cis elements in pre-mRNAs and their cognate binding partners, mainly RNA-binding proteins (RBPs). Splicing-regulatory RBPs recruited to their respective binding sites can have positive or negative effects on the splicing of different exons or splice sites. Many RBPs with largely ubiquitous expression in different tissues and cells have been shown to have broad impacts on splicing and important cell functions, such as SR and hnRNP protein families (4). However, several tissue-specific RBPs, such as NOVA, PTBP2 (nPTB), MBNL, and RBFOX proteins, have recently been described as having important roles as essential regulators of tissue-or cell-type-specific splicing (5-9). In order to further define a "splicing code" that controls broad patterns of tissue-specific splicing, as well as those that occur during developmental transitions, it is essential to characterize in greater detail how these tissue-specific regulators fine-tune AS programs combinatorially with more ubiquitously expressed splicing regulators (10).The epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells transdifferentiate into mesenchymal cells, which involves extensive changes at the cellular ...

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“…Copy-number loss was more frequently observed than copy-number gain for 54 genes (Supplementary Table S4). A total of 17 genes had copy-number loss in more than 20% of cases (Table 1), and these genes included well-established tumor-suppressor genes such as PTEN and QKI (17,18), as well as genes that had been previously unreported as tumor suppressors. Notably, four genes (VTI1A, DDX50, MLLT10, and LARP4B) showed heterozygous deletion in more than 80% of glioblastoma samples (Table 1, %Hetero_Del).…”

Section: Larp4b Is a Candidate Tumor-suppressor Gene In Gliomamentioning

confidence: 99%

Identification of RNA-Binding Protein LARP4B as a Tumor Suppressor in Glioma

Koso

Sheridan

et al. 2016

Cancer Research

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Transposon-based insertional mutagenesis is a valuable method for conducting unbiased forward genetic screens to identify cancer genes in mice. We used this system to elucidate factors involved in the malignant transformation of neural stem cells into glioma-initiating cells. We identified an RNAbinding protein, La-related protein 4b (LARP4B), as a candidate tumor-suppressor gene in glioma. LARP4B expression was consistently decreased in human glioma stem cells and cell lines compared with normal neural stem cells. Moreover, heterozygous deletion of LARP4B was detected in nearly 80% of glioblastomas in The Cancer Genome Atlas database. LARP4B loss was also associated with low expression and poor patient survival. Overexpression of LARP4B in glioma cell lines strongly inhibited proliferation by inducing mitotic arrest and apoptosis in four of six lines as well as in two patient-derived glioma stem cell populations. The expression levels of CDKN1A and BAX were also upregulated upon LARP4B overexpression, and the growth-inhibitory effects were partially dependent on p53 (TP53) activity in cells expressing wild-type, but not mutant, p53. We further found that the La module, which is responsible for the RNA chaperone activity of LARP4B, was important for the growth-suppressive effect and was associated with BAX mRNA. Finally, LARP4B depletion in p53 and Nf1-deficient mouse primary astrocytes promoted cell proliferation and led to increased tumor size and invasiveness in xenograft and orthotopic models. These data provide strong evidence that LARP4B serves as a tumor-suppressor gene in glioma, encouraging further exploration of the RNA targets potentially involved in LARP4B-mediatd growth inhibition. Cancer Res; 76(8); 2254-64. Ó2016 AACR.

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STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA

Cited by 107 publications

References 56 publications

Developmental genetics of the mouse <i>t</i>-complex

Developmental genetics of the mouse <i>t</i>-complex

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Identification of RNA-Binding Protein LARP4B as a Tumor Suppressor in Glioma

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