DNA polymerase η is regulated by poly(rC)-binding protein 1 via mRNA stability

Ren, Cong; Cho, Seong Jun; Jung, Yong Sam; Chen, Xinbin

doi:10.1042/bj20141164

Cited by 17 publications

(13 citation statements)

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“…The hnRNP E1 together with hnRNP E2 control the p21 WAF mRNA half-life and therefore regulate the cell cycle via a p53-independent mechanism (Waggoner et al 2009 ). Additionally, hnRNP E1 increases the mRNA stability of DNA polymerase η , which is a target of p53 tumor suppression (Ren et al 2014 ). The p63, another transcription factor and a p53 family protein, was also identified to be a target of hnRNP E1 mRNA stabilization (Cho et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The hnRNP family: insights into their role in health and disease

2016

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Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins (RBPs) that contribute to multiple aspects of nucleic acid metabolism including alternative splicing, mRNA stabilization, and transcriptional and translational regulation. Many hnRNPs share general features, but differ in domain composition and functional properties. This review will discuss the current knowledge about the different hnRNP family members, focusing on their structural and functional divergence. Additionally, we will highlight their involvement in neurodegenerative diseases and cancer, and the potential to develop RNA-based therapies.

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Section: Discussionmentioning

confidence: 99%

The hnRNP family: insights into their role in health and disease

2016

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“…As a RNA-binding protein, PCBP1 can directly regulate gene expression in posttranscription by binding to 3’-UTR (e.g. AR, p21, p63, eNOS, POLH ) [ 7 – 10 , 50 ] or 5’-UTRs (e.g. c-myc, PRL-3, EV71 ) [ 6 , 11 , 12 ] of various mRNAs, although the molecular details of such regulation remain to be structurally determined.…”

Section: Discussionmentioning

confidence: 99%

“…It is believed that PCBP1 can bind to multiple transcripts, such as POLH (DNA polymerase η) to control its expression via mRNA stability [ 50 ], and POLH loss is responsible for the human cancer-prone syndrome XPV, but there is no in vivo and clinical result to further support this notion. Here, our both in vitro and in vivo results implied that p27 could be likely the most effective downstream target of PCBP1 in inhibition of tumorigenesis, since the cell proliferation and tumorigenesis inhibition imposed by PCBP1 can almost be blocked by the additional knockdown of p27 in the same cells.…”

Section: Discussionmentioning

confidence: 99%

PCBP1 depletion promotes tumorigenesis through attenuation of p27Kip1 mRNA stability and translation

Shi

Yuan

et al. 2018

J Exp Clin Cancer Res

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BackgroundPoly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive.MethodsWe performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases.ResultsWe identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3’UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database.ConclusionOur results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0840-1) contains supplementary material, which is available to authorized users.

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“…The primers to amplify various probes are listed in supplemental Table 1. REMSA were performed as previously described (29). Briefly, 32 P-labeled probes were incubated with recombinant protein in a binding buffer (10 mM HEPES-KOH at pH 7.5, 90 mM potassium acetate, 1.5 mM magnesium acetate, 2.5 mM DTT, 40 units of RNase inhibitor) at 25°C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

RNA-binding Protein PCBP2 Regulates p73 Expression and p73-dependent Antioxidant Defense

Ren¹,

Zhang²,

Yan

et al. 2016

Journal of Biological Chemistry

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TAp73, a member of the p53 family tumor suppressors, plays a critical rule in tumor suppression and neuronal development. However, how p73 activity is controlled at the posttranscriptional level is not well understood. Here, we showed that TAp73 activity is regulated by RNA-binding protein PCBP2. Specifically, we found that knockdown or knock-out of PCBP2 reduces, whereas ectopic expression of PCBP2 increases, TAp73 expression. We also showed that PCBP2 is necessary for p73 mRNA stability via the CU-rich elements in p73 3 -UTR. To uncover the biological relevance of PCBP2-regulated TAp73 expression, we showed that ectopic expression of PCBP2 inhibits, whereas knockdown or knock-out of PCBP2 increases, the production of reactive oxygen species (ROS) in a TAp73-dependent manner. Additionally, we found that glutaminase 2 (GLS2), a modulator of p73-dependent antioxidant defense, is also involved in PCBP2-regulated ROS production. Moreover, we generated PCBP2-deficient mice and primary mouse embryonic fibroblasts (MEFs) and showed that loss of PCBP2 leads to decreased p73 expression and, subsequently, increased ROS production and accelerated cellular senescence. Together, our data suggest that PCBP2 regulates p73 expression via mRNA stability and p73-dependent biological function in ROS production and cellular senescence.p73, along with p53 and p63, consists of the p53 family and is expressed as multiple isoforms (1). Through alternative splicing, at least seven isoforms (␣, ␤, ␥, ␦, ⑀, , and ) are expressed. In addition, due to the usage of two different promoters, p73 is expressed as two different isoforms, TAp73 and ⌬Np73. The TAp73 isoform is transcribed from the upstream P1 promoter and contains an N-terminal activation domain conserved in p53, whereas the ⌬Np73 isoform is produced by the downstream P2 promoter and, thus, N-terminally truncated. Consequently, TAp73, like p53, regulates an array of genes for tumor suppression (2). Indeed, mice deficient in TAp73 are prone to spontaneous tumors and premature aging (3, 4). By contrast, ⌬Np73 acts as an oncoprotein against TAp73 as well as p53 (5, 6). For example, ⌬Np73 promotes cell immortalization in mouse embryonic fibroblasts (MEFs) 5 and cooperates with oncogenic Ras in cell transformation in vitro and in vivo (7). In addition, mice deficient in ⌬Np73 do not develop tumors but exhibit delayed onset of moderate neurodegeneration (8, 9). The opposing functions of TAp73 and ⌬Np73 create more complicated issues for the role of p73 in cancer. Therefore, it is important to understand how p73 expression is controlled, which would advance our understanding of p73 biology and shed light on the development of novel strategy for cancer management.The poly(rC)-binding protein 2 (PCBP2) is a RNA-binding protein and belongs to the PCBP family. Members of PCBP family are characterized by their affinity to single-stranded poly(C) motifs in their target mRNAs (10). PCBP2 is a multifunctional protein and regulates gene expression at multiple levels including mRNA metabolism an...

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DNA polymerase η is regulated by poly(rC)-binding protein 1 via mRNA stability

Cited by 17 publications

References 54 publications

The hnRNP family: insights into their role in health and disease

The hnRNP family: insights into their role in health and disease

PCBP1 depletion promotes tumorigenesis through attenuation of p27Kip1 mRNA stability and translation

RNA-binding Protein PCBP2 Regulates p73 Expression and p73-dependent Antioxidant Defense

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