PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Yang, Bin; Hu, Pei-Shan; Lin, Xihua; Han, Wei; Zhu, Liyuan; Tan, Xiaochao; Ye, Fei; Wang, Guanzhou; Wu, Fan; Yin, Bin; Bao, Zhaoshi; Jiang, Tao; Yuan, Jing; Qiang, Boqin; Peng, Xiaozhong

doi:10.1007/s00018-015-1938-7

Cited by 33 publications

(26 citation statements)

References 51 publications

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“…Previous reports have shown that PTBP1 acts as a tumor promoter in several cancers [19][20][21]. Our results also demonstrated that PTBP1 konckdown inhibits the viability (See figure on previous page.)…”

Section: Ptbp1 Functions Downstream Of Lucat1 In Crc Under Hypoxiasupporting

confidence: 81%

Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response

et al. 2020

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Background: Hypoxic tumors are refractory to DNA damage drugs. However, the underlying mechanism has yet to be elucidated. We aimed to identify lncRNAs that upregulated under hypoxia and their effects on colorectal cancer (CRC). Methods: CRC cells were treated with 1% O 2 to identify lncRNAs that upregulated under hypoxia. We integrated these lncRNAs with RNA-seq of 4 paired CRC tissues and TCGA data to get candidate lncRNAs. Multiple in vitro and in vivo assays were used to explore the role of LUCAT1 in CRC. Results: We identified a hypoxia-induced lncRNA LUCAT1 that facilitated the growth of CRC cells and contributed to drug resistance of CRC cells both in vitro and in vivo. Mechanically, LUCAT1 interacts with polypyrimidine tract binding protein 1 (PTBP1) in CRC cells, facilitates the association of a set of DNA damage related genes with PTBP1, thus resulting in altered alternative splicing of these genes. Moreover, ectopic expression of PTBP1 in CRC cells with knockdown of LUCAT1 abrogated the effects induced by LUCAT1 knockdown. Chemotherapeutics drug combined with LUCAT1 knockdown via antisense oligonucleotides (ASO) would get a better outcome in vivo, compared with group treated with chemotherapeutic drug only. Notably, LUCAT1 is upregulated in CRC tissues, compared to adjacent normal tissues; and CRC patients with higher LUCAT1 have a worse prognosis and poorly responded to chemotherapy in the clinic. Conclusions: Our data suggested CRC cells utilizes LUCAT1 to develop resistance to DNA damage drugs, and disrupting the LUCAT1/PTBP1 axis might be a promising therapeutic strategy for refractory hypoxic tumors.

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Section: Ptbp1 Functions Downstream Of Lucat1 In Crc Under Hypoxiasupporting

confidence: 81%

Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response

et al. 2020

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“…The remaining 6 candidates did not show evidence of binding near editing sites ( Figure 2D ). Included in this last group is PTBP1, which has been shown to be a translational regulator of ADAR (Yang et al, 2015); this role may explain why it physically interacts with ADAR but does not bind near editing sites. For the 13 RBPs that bound RNA at or near editing sites, we compared the positions of their binding sites to the editing sites that they regulated to determine whether their knockdown affected editing levels specifically at the sites that were bound by the proteins.…”

Section: Resultsmentioning

confidence: 99%

“…These proteins may help ADAR proteins perform their other known functions in the cell such as miRNA regulation, or as yet unknown editing-independent functions of ADARs. They may also regulate the translation of ADARs, similar to PTBP1, which can activate the translation of ADAR-p110 through an IRES-like element (Yang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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13Adenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to 14 inosine. While many RNA editing sites are known, few trans regulators have been identified. We 15 perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 16 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. 17Using ENCODE data we validate and characterize a subset of the novel interactors as global or 18 site-specific RNA editing regulators. Our set of novel trans regulators includes all four members 19 of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that 20 these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a 21 global negative regulator of editing. This work demonstrates the broad roles RNA binding 22 proteins play in regulating editing levels and establishes DZF-domain containing proteins as a 23 group of highly influential RNA editing regulators. 24 25 47 the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily 48 responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et 49 al., 2017). ADAR2-regulated sites in non-repetitive regions include a number of editing events 50 that alter the protein-coding sequences of neuronal RNAs, including GluR2, which encodes a 51 glutamate receptor in which RNA editing is necessary for its proper function. Further 52 demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is 53 associated with multiple neurological diseases, including amyotrophic lateral sclerosis, 54 astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al., 2019). 55Maintaining RNA editing levels is critical for human health, but how RNA editing levels are 56 regulated at specific editing sites across tissues and development is poorly understood. 58While RNA sequence and structure are critical determinants of editing levels, studies querying 59 tissue-specific and developmental-stage-specific editing levels show that the level of editing at 60 the same editing site can vary greatly between individuals and tissues. These changes do not 61 always correlate with ADAR mRNA or protein expression, suggesting a complex regulation of 62 editing events by factors other than ADAR proteins (Sapiro et al., 2019; Tan et al., 2017; 63 Wahlstedt et al., 2009). Recently, an analysis of proteins with an RNA-binding domain profiled 64 by ENCODE suggested that RNA-binding proteins play a role in RNA editing regulation. Further, 65 in mammals, a small number of trans regulators of editing have been identified through 66 functional experiments (Quinones-Valdez et al., 2019). Some of these trans regulators of editing 67 are site-specific, in that they affect editing levels at only a small subset of editing sites. These 68 include RNA binding proteins such as DHX15, HNRNPA2/B1, RPS14, TDP-43, Drosha and 69 Ro60 (Garncarz et al., 2013; Quinones-Valdez ...

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“…Several studies revealed that trans-acting factors (ITAFs) were necessary for the activity of cellular and viral IRESs [ 12 , 13 , 14 ]. For instance, La autoantigen (La) and polyprymidine tract binding protein 1 (PTBP1) are two important ITAFs, which conjugated to the IRES region of mRNA and induced the conformational change to facilitate the recruitment of the ribosome for IRES [ 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

La Autoantigen Induces Ribosome Binding Protein 1 (RRBP1) Expression through Internal Ribosome Entry Site (IRES)-Mediated Translation during Cellular Stress Condition

Gao

Zhu

et al. 2016

IJMS

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The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA has a long 5′ untranslated region that potentially formed a stable secondary structure. In this study, we show that the 5′ UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). Moreover, the RRBP1 expression is induced by chemotherapeutic drug paclitaxel or adriamycin in human hepatocellular carcinoma cells and accompanied with the increased expression of La autoantigen (La), which binds to RRBP1 IRES element and facilitates translation initiation. Interestingly, we found IRES-mediated RRBP1 translation is also activated during serum-starvation condition which can induce cytoplasmic localization of La. After mapping the entire RRBP1 5′ UTR, we determine the core IRES activity is located between nt-237 and -58. Furthermore, two apical GARR loops within the functional RRBP1 IRES elements may be important for La binding. These results strongly suggest an important role for IRES-dependent translation of RRBP1 mRNA in hepatocellular carcinoma cells during cellular stress conditions.

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PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Cited by 33 publications

References 51 publications

Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response

Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

La Autoantigen Induces Ribosome Binding Protein 1 (RRBP1) Expression through Internal Ribosome Entry Site (IRES)-Mediated Translation during Cellular Stress Condition

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