scholarly journals Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal epithelial apoptosis

2010 ◽  
Vol 426 (3) ◽  
pp. 293-306 ◽  
Author(s):  
Peng-Yuan Wang ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
Lan Xiao ◽  
...  
Keyword(s):  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Transcriptional Level ◽  
Intestinal Epithelial ◽  
Cellular Functions ◽  
Mitogen Activated Protein ◽  
Hu Antigen R ◽  
Post Transcriptional Regulation

MEK-1 [MAPK (mitogen-activated protein kinase) kinase-1] is an important signal transducing enzyme that is implicated in many aspects of cellular functions. In the present paper, we report that cellular polyamines regulate MEK-1 expression at the post-transcriptional level through the RNA-binding protein HuR (Hu-antigen R) in IECs (intestinal epithelial cells). Decreasing the levels of cellular polyamines by inhibiting ODC (ornithine decarboxylase) stabilized MEK-1 mRNA and promoted its translation through enhancement of the interaction between HuR and the 3′-untranslated region of MEK-1 mRNA, whereas increasing polyamine levels by ectopic ODC overexpression destabilized the MEK-1 transcript and repressed its translation by reducing the abundance of HuR–MEK-1 mRNA complex; neither intervention changed MEK-1 gene transcription via its promoter. HuR silencing rendered the MEK-1 mRNA unstable and inhibited its translation, thus preventing increases in MEK-1 mRNA and protein in polyamine-deficient cells. Conversely, HuR overexpression increased MEK-1 mRNA stability and promoted its translation. Inhibition of MEK-1 expression by MEK-1 silencing or HuR silencing prevented the increased resistance of polyamine-deficient cells to apoptosis. Moreover, HuR overexpression did not protect against apoptosis if MEK-1 expression was silenced. These results indicate that polyamines destabilize the MEK-1 mRNA and repress its translation by inhibiting the association between HuR and the MEK-1 transcript. Our findings indicate that MEK-1 is a key effector of the HuR-elicited anti-apoptotic programme in IECs.

scholarly journals Role of the RNA-binding Protein Nrd1 and Pmk1 Mitogen-activated Protein Kinase in the Regulation of Myosin mRNA Stability in Fission Yeast

2009 ◽  
Vol 20 (9) ◽  
pp. 2473-2485 ◽  
Author(s):  
Ryosuke Satoh ◽  
Takahiro Morita ◽  
Hirofumi Takada ◽  
Ayako Kita ◽  
Shunji Ishiwata ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fission Yeast ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Myosin Ii ◽  
Rna Binding Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Myosin II is an essential component of the actomyosin contractile ring and plays a crucial role in cytokinesis by generating the forces necessary for contraction of the actomyosin ring. Cdc4 is an essential myosin II light chain in fission yeast and is required for cytokinesis. In various eukaryotes, the phosphorylation of myosin is well documented as a primary means of activating myosin II, but little is known about the regulatory mechanisms of Cdc4. Here, we isolated Nrd1, an RNA-binding protein with RNA-recognition motifs, as a multicopy suppressor of cdc4 mutants. Notably, we demonstrated that Nrd1 binds and stabilizes Cdc4 mRNA, thereby suppressing the cytokinesis defects of the cdc4 mutants. Importantly, Pmk1 mitogen-activated protein kinase (MAPK) directly phosphorylates Nrd1, thereby negatively regulating the binding activity of Nrd1 to Cdc4 mRNA. Consistently, the inactivation of Pmk1 MAPK signaling, as well as Nrd1 overexpression, stabilized the Cdc4 mRNA level, thereby suppressing the cytokinesis defects associated with the cdc4 mutants. In addition, we demonstrated the cell cycle–dependent regulation of Pmk1/Nrd1 signaling. Together, our results indicate that Nrd1 plays a role in the regulation of Cdc4 mRNA stability; moreover, our study is the first to demonstrate the posttranscriptional regulation of myosin expression by MAPK signaling.

The RNA-binding protein HuR stabilizes survivin mRNA in human oesophageal epithelial cells

2011 ◽  
Vol 437 (1) ◽  
pp. 89-96 ◽  
Author(s):  
James M. Donahue ◽  
Elizabeth T. Chang ◽  
Lan Xiao ◽  
Peng-Yuan Wang ◽  
Jaladanki N. Rao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Oesophageal Cancer ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Survivin Expression ◽  
Transcriptional Level ◽  
Survivin Mrna ◽  
Hu Antigen R

Overexpression of survivin, a member of the IAP (inhibitor of apoptosis) family, has been correlated with poorer outcomes in multiple malignancies, including oesophageal cancer. The regulatory mechanisms, particularly at the post-transcriptional level, involved in survivin overexpression are not well understood. Previous work from our group has shown that the RNA-binding protein HuR (Hu antigen R), which is also overexpressed in several malignancies, stabilizes the mRNA of XIAP (X-linked IAP), another IAP family member. In the present study, we demonstrate the binding of HuR to a 288 bp fragment in the 3′-UTR (untranslated region) of survivin mRNA in human oesophageal epithelial cells. Unexpectedly, overexpression of HuR led to a decrease in survivin expression. This was associated with decreased survivin mRNA and promoter activity, suggesting a decrease in transcription. Levels of p53, a negative transcriptional regulator of survivin, increased following HuR overexpression, in conjunction with enhanced p53 mRNA stability. Silencing p53 prior to HuR overexpression resulted in increased survivin protein and mRNA stability. These results demonstrate that, in the absence of p53, HuR overexpression results in increased survivin mRNA stability and protein expression. This provides an additional explanation for the increased survivin expression observed in oesophageal cancer cells that have lost p53.

scholarly journals p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR

2009 ◽  
Vol 18 (21) ◽  
pp. 4035-4045 ◽  
Author(s):  
Faraz Farooq ◽  
Sylvia Balabanian ◽  
Xuejun Liu ◽  
Martin Holcik ◽  
Alex MacKenzie
Keyword(s):  
Protein Kinase ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals Post-transcriptional regulation of Wnt co-receptor LRP6 and RNA-binding protein HuR by miR-29b in intestinal epithelial cells

2016 ◽  
Vol 473 (11) ◽  
pp. 1641-1649 ◽  
Author(s):  
Yanwu Li ◽  
Gang Chen ◽  
Jun-Yao Wang ◽  
Tongtong Zou ◽  
Lan Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Rna Binding ◽  
Intestinal Epithelial Cells ◽  
Binding Protein ◽  
Low Density Lipoprotein ◽  
Rna Binding Protein ◽  
Density Lipoprotein ◽  
Transcriptional Level ◽  
Intestinal Epithelial ◽  
Repressive Effect

MicroRNAs (miRNAs) control gene expression by binding to their target mRNAs for degradation and/or translation repression and are implicated in many aspects of cellular physiology. Our previous study shows that miR-29b acts as a biological repressor of intestinal mucosal growth, but its exact downstream targets remain largely unknown. In the present study, we found that mRNAs, encoding Wnt co-receptor LRP6 (low-density lipoprotein-receptor-related protein 6) and RNA-binding protein (RBP) HuR, are novel targets of miR-29b in intestinal epithelial cells (IECs) and that expression of LRP6 and HuR is tightly regulated by miR-29b at the post-transcriptional level. miR-29b interacted with both Lrp6 and HuR mRNAs via their 3′-UTRs and inhibited LRP6 and HuR expression by destabilizing Lrp6 and HuR mRNAs and repressing their translation. Studies using heterologous reporter constructs revealed a greater repressive effect of miR-29b through a single binding site in the Lrp6 or HuR 3′-UTR, whereas deletion mutation of this site prevented miR-29b-induced repression of LRP6 and HuR expression. Repression of HuR by miR-29b in turn also contributed to miR-29b-induced LRP6 inhibition, since ectopic overexpression of HuR in cells overexpressing miR-29b restored LRP6 expression to near normal levels. Taken together, our results suggest that miR-29b inhibits expression of LRP6 and HuR post-transcriptionally, thus playing a role in the regulation of IEC proliferation and intestinal epithelial homoeostasis.

scholarly journals The RNA-Binding Protein PCBP1 Functions as a Tumor Suppressor in Prostate Cancer by Inhibiting Mitogen Activated Protein Kinase 1

2018 ◽  
Vol 48 (4) ◽  
pp. 1747-1754 ◽  
Author(s):  
Yingying Zhang ◽  
Lin Meng ◽  
Lin Xiao ◽  
Ruiwang Liu ◽  
Zhonghai Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Kinase ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Mitogen Activated Protein

Background/Aims: Poly r(C) binding protein (PCBP) 1 or heterogeneous ribonucleoprotein (hnRNP) E1 is a RNA binding protein functional in multiple biological processes. In prostate cancer (PCa), PCBP1 loss was shown to be involved with increased stemness in PCacells; however, the underlying mechanism remains unclear. Method: The role of PCBP1 in prostate tumor formationwas determined by xenograft assays. Immunoprecipitationand mass spectrometry were performed to find the pathways altered after PCBP1 knockdown. Cell proliferation, migration, invasion, and soft agar colony formationassays and xenograft assays were used to determine the role of target protein pathogenesis regulation and formation of PCa. QRT-PCR was performedto quantify relative mRNA expression. Results: The expression of mitogen activated protein kinase 1 (MAPK1) or extracellular signal regulated kinase 2 (ERK2) was increased following PCBP1 loss. Attenuation of MAPK1 inhibited in vitro and in vivo tumorigenicity and metastasis in PCa cell line, PC3. Overexpression of MAPK1 in the PC3 cells increased the tumorigenicity and metastasis. Analysis of PCBP1 and MAPK1 mRNA levels in 25 PCa patients compared to tumor-adjacent normal tissue confirmed an inverse correlation between PCBP1 and MAPK1 expression. Conclusions: PCBP1 can act as a suppressor of tumor in prostate epithelial cells by inhibiting MAPK1 expression.

scholarly journals Transcriptional regulation of importin-α1 by JunD modulates subcellular localization of RNA-binding protein HuR in intestinal epithelial cells

2016 ◽  
Vol 311 (6) ◽  
pp. C874-C883 ◽  
Author(s):  
Yan Xu ◽  
Jie Chen ◽  
Lan Xiao ◽  
Hee Kyoung Chung ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Subcellular Localization ◽  
Rna Binding ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Intestinal Epithelial ◽  
Mucosal Regeneration ◽  
Importin Α

The RNA-binding protein HuR is crucial for normal intestinal mucosal regeneration by modulating the stability and translation of target mRNAs, but the exact mechanism underlying HuR trafficking between the cytoplasm and nucleus remains largely unknown. Here we report a novel function of transcription factor JunD in the regulation of HuR subcellular localization through the control of importin-α1 expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically inhibited importin-α1 at the transcription level, and this repression is mediated via interaction with CREB-binding site that was located at the proximal region of importin-α1 promoter. Reduction in the levels of importin-α1 by JunD increased cytoplasmic levels of HuR, although it failed to alter whole cell HuR levels. Increased levels of endogenous JunD by depleting cellular polyamines also inhibited importin-α1 expression and increased cytoplasmic HuR levels, whereas JunD silencing rescued importin-α1 expression and enhanced HuR nuclear translocation in polyamine-deficient cells. Moreover, importin-α1 silencing protected IECs against apoptosis, which was prevented by HuR silencing. These results indicate that JunD regulates HuR subcellular distribution by downregulating importin-α1, thus contributing to the maintenance of gut epithelium homeostasis.

Sa1436 RNA-Binding Protein HuR Regulates Intestinal Epithelial Regeneration by Altering Subcellular Distribution of Rac1

2016 ◽  
Vol 150 (4) ◽  
pp. S314-S315
Author(s):  
Lan Liu ◽  
Rao N. Jaladanki ◽  
Lan Xiao ◽  
Hee Kyoung Chung ◽  
Jing Wu ◽  
...  
Keyword(s):  
Subcellular Distribution ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Intestinal Epithelial ◽  
Epithelial Regeneration

scholarly journals Genomic Analyses of the RNA-binding Protein Hu Antigen R (HuR) Identify a Complex Network of Target Genes and Novel Characteristics of Its Binding Sites

2011 ◽  
Vol 286 (43) ◽  
pp. 37063-37066 ◽  
Author(s):  
Philip J. Uren ◽  
Suzanne C. Burns ◽  
Jianhua Ruan ◽  
Kusum K. Singh ◽  
Andrew D. Smith ◽  
...  
Keyword(s):  
Complex Network ◽  
Binding Sites ◽  
Target Genes ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Genomic Analyses ◽  
Hu Antigen R

scholarly journals The Putative RNA-Binding Protein Nrp1 Promotes the Loading of Kinesin-14/Klp2 to the Mitotic Spindle and Is Sequestered Into Heat-Induced Protein Aggregates in Fission Yeast

2021 ◽  
Author(s):  
Masashi Yukawa ◽  
Mitsuki Ohishi ◽  
Yusuke Yamada ◽  
Takashi Toda
Keyword(s):  
Fission Yeast ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Protein Aggregates ◽  
Associated Proteins ◽  
Spindle Microtubules ◽  
The Stability ◽  
And Function ◽  
Post Transcriptional Regulation

Cells form a bipolar spindle during mitosis to ensure accurate chromosome segregation. Proper spindle architecture is established by a set of kinesin motors and microtubule-associated proteins. In most eukaryotes, kinesin-5 motors are essential for this process, and genetic or chemical inhibition of their activity leads to the emergence of monopolar spindles and cell death. However, these deficiencies can be rescued by simultaneous inactivation of kinesin-14 motors, as they counteract kinesin-5. We conducted detailed genetic analyses in fission yeast to understand the mechanisms driving spindle assembly in the absence of kinesin-5. Here we show that deletion of the nrp1 gene, which encodes a putative RNA-binding protein with unknown function, can rescue temperature sensitivity caused by cut7-22, a fission yeast kinesin-5 mutant. Interestingly, kinesin-14/Klp2 levels on the spindles in the cut7 mutants were significantly reduced by the nrp1 deletion, although the total levels of Klp2 and the stability of spindle microtubules remained unaffected. Moreover, RNA-binding motifs of Nrp1 are essential for its cytoplasmic localization and function. We have also found that a portion of Nrp1 is spatially and functionally sequestered by chaperone-based protein aggregates upon mild heat stress and limits cell division at high temperatures. We propose that Nrp1 might be involved in post-transcriptional regulation through its RNA-binding ability to promote the loading of Klp2 on the spindle microtubules.

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