scholarly journals Polyamines Regulate the Stability of Activating Transcription Factor-2 mRNA through RNA-binding Protein HuR in Intestinal Epithelial Cells

2007 ◽  
Vol 18 (11) ◽  
pp. 4579-4590 ◽  
Author(s):  
Lan Xiao ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
Bernard S. Marasa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Rna Binding ◽  
Binding Protein ◽  
Critical Role ◽  
Rna Binding Protein ◽  
Gene Promoter ◽  
Protein Levels ◽  
Ribonucleoprotein Complexes ◽  
Activating Transcription Factor ◽  
The Stability

Maintenance of intestinal mucosal epithelial integrity requires polyamines that modulate the expression of various genes involved in cell proliferation and apoptosis. Recently, polyamines were shown to regulate the subcellular localization of the RNA-binding protein HuR, which stabilizes its target transcripts such as nucleophosmin and p53 mRNAs. The activating transcription factor-2 (ATF-2) mRNA encodes a member of the ATF/CRE-binding protein family of transcription factors and was computationally predicted to be a target of HuR. Here, we show that polyamines negatively regulate ATF-2 expression posttranscriptionally and that polyamine depletion stabilizes ATF-2 mRNA by enhancing the interaction of the 3′-untranslated region (UTR) of ATF-2 with cytoplasmic HuR. Decreasing cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine increased the levels of ATF-2 mRNA and protein, whereas increasing polyamines by ectopic ODC overexpression repressed ATF-2 expression. Polyamine depletion did not alter transcription via the ATF-2 gene promoter but increased the stability of ATF-2 mRNA. Increased cytoplasmic HuR in polyamine-deficient cells formed ribonucleoprotein complexes with the endogenous ATF-2 mRNA and specifically bound to 3′-UTR of ATF-2 mRNA on multiple nonoverlapping 3′-UTR segments. Adenovirus-mediated HuR overexpression elevated ATF-2 mRNA and protein levels, whereas HuR silencing rendered the ATF-2 mRNA unstable and prevented increases in ATF-2 mRNA and protein. Furthermore, inhibition of ATF-2 expression prevented the increased resistance of polyamine-deficient cells to apoptosis induced by treatment with tumor necrosis factor-α and cycloheximide. These results indicate that polyamines modulate the stability of ATF-2 mRNA by altering cytoplasmic HuR levels and that polyamine-modulated ATF-2 expression plays a critical role in regulating epithelial apoptosis.

scholarly journals Critical role of tristetraprolin and AU‐rich element RNA‐binding protein 1 in the suppression of cancer cell growth by globular adiponectin

FEBS Open Bio ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 1964-1976 ◽  
Author(s):  
Nirmala Tilija Pun ◽  
Amrita Khakurel ◽  
Aastha Shrestha ◽  
Sang‐Hyun Kim ◽  
Pil‐Hoon Park
Keyword(s):  
Cell Growth ◽  
Cancer Cell ◽  
Rna Binding ◽  
Binding Protein ◽  
Critical Role ◽  
Rna Binding Protein ◽  
Cancer Cell Growth ◽  
Globular Adiponectin

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.

CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1

2021 ◽  
Vol 221 (1) ◽  
Author(s):  
Xue Deng ◽  
Xing Sun ◽  
Wenkai Yue ◽  
Yongjia Duan ◽  
Rirong Hu ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Down Regulation ◽  
Protein Levels ◽  
Modifying Effect

The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy–endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2BIntron5 mutation. In this study, we identify CHMP2B as a modifier of TDP-43–mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2BIntron5 causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation.

scholarly journals A potential role for a novel ZC3H5 complex in regulating mRNA translation in Trypanosoma brucei

2020 ◽  
Vol 295 (42) ◽  
pp. 14291-14304
Author(s):  
Kathrin Bajak ◽  
Kevin Leiss ◽  
Christine Clayton ◽  
Esteban Erben
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Affinity Purification ◽  
Critical Role ◽  
Rna Binding Protein ◽  
Mrna Translation

In Trypanosoma brucei and related kinetoplastids, gene expression regulation occurs mostly posttranscriptionally. Consequently, RNA-binding proteins play a critical role in the regulation of mRNA and protein abundance. Yet, the roles of many RNA-binding proteins are not understood. Our previous research identified the RNA-binding protein ZC3H5 as possibly involved in gene repression, but its role in controlling gene expression was unknown. We here show that ZC3H5 is an essential cytoplasmic RNA-binding protein. RNAi targeting ZC3H5 causes accumulation of precytokinetic cells followed by rapid cell death. Affinity purification and pairwise yeast two-hybrid analysis suggest that ZC3H5 forms a complex with three other proteins, encoded by genes Tb927.11.4900, Tb927.8.1500, and Tb927.7.3040. RNA immunoprecipitation revealed that ZC3H5 is preferentially associated with poorly translated, low-stability mRNAs, the 5′-untranslated regions and coding regions of which are enriched in the motif (U/A)UAG(U/A). As previously found in high-throughput analyses, artificial tethering of ZC3H5 to a reporter mRNA or other complex components repressed reporter expression. However, depletion of ZC3H5 in vivo caused only very minor decreases in a few targets, marked increases in the abundances of very stable mRNAs, an increase in monosomes at the expense of large polysomes, and appearance of “halfmer” disomes containing two 80S subunits and one 40S subunit. We speculate that the ZC3H5 complex might be implicated in quality control during the translation of suboptimal open reading frames.

Cold-induced RNA-binding protein (CIRBP) regulates the expression of Src-associated during mitosis of 68 kDa (Sam68) and extracellular signal-regulated kinases (ERK) during heat stress-induced testicular injury

2020 ◽  
Vol 32 (18) ◽  
pp. 1357
Author(s):  
Chengcheng Xu ◽  
Dandan Ke ◽  
Liping Zou ◽  
Nianyu Li ◽  
Yingying Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heat Stress ◽  
Protein Expression ◽  
Rna Binding ◽  
Cell Model ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Testicular Injury

In this study, the ability of cold-induced RNA-binding protein (CIRBP) to regulate the expression of Src-associated during mitosis of 68 kDa (Sam68) and extracellular signal-regulated kinases (ERK) in the mouse testis and mouse primary spermatocytes (GC-2spd cell line) before and after heat stress was examined to explore the molecular mechanism by which CIRBP decreases testicular injury. A mouse testicular hyperthermia model, a mouse primary spermatocyte hyperthermia model and a low CIRBP gene-expression cell model were constructed and their relevant parameters were analysed. The mRNA and protein levels of CIRBP and Sam68 were significantly decreased in the 3-h and 12-h testicular heat-stress groups, extracellular signal-regulated kinase 1/2 (ERK1/2) protein expression was not significantly affected but phospho-ERK1/2 protein levels were significantly decreased. GC-2spd cellular heat-stress results showed that the mRNA and protein concentrations of CIRBP and Sam68 were reduced 48h after heat stress. In the low CIRBP gene-expression cell model, CIRBP protein expression was significantly decreased. Sam68 mRNA expression was significantly decreased only at the maximum transfection concentration of 50nM and Sam68 protein expression was not significantly affected. These findings suggest that CIRBP may regulate the expression of Sam68 at the transcriptional level and the expression of phospho-ERK1/2 protein, both of which protect against heat-stress-induced testicular injury in mice.

scholarly journals Nuclear depletion of RNA binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Sandra Diaz-Garcia ◽  
Vivian I. Ko ◽  
Sonia Vazquez-Sanchez ◽  
Ruth Chia ◽  
Olubankole Aladesuyi Arogundade ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Loss Of Function ◽  
Cryptic Exon ◽  
Protein Levels ◽  
Sporadic Als ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive fatal neurodegenerative disease caused by loss of motor neurons and characterized neuropathologically in almost all cases by nuclear depletion and cytoplasmic aggregation of TDP-43, a nuclear RNA binding protein (RBP). We identified ELAVL3 as one of the most downregulated genes in our transcriptome profiles of laser captured microdissection of motor neurons from sporadic ALS nervous systems and the top dysregulated RBPs. Neuropathological characterizations showed ELAVL3 nuclear depletion in a great percentage of remnant motor neurons, sometimes accompanied by cytoplasmic accumulations. These abnormalities were common in sporadic cases with and without intermediate expansions in ATXN2 and familial cases carrying mutations in C9orf72 and SOD1. Depletion of ELAVL3 occurred at both the RNA and protein levels and a short protein isoform was identified but it is not related to a TDP-43-dependent cryptic exon in intron 3. Strikingly, ELAVL3 abnormalities were more frequent than TDP-43 abnormalities and occurred in motor neurons still with normal nuclear TDP-43 present, but all neurons with abnormal TDP-43 also had abnormal ELAVL3. In a neuron-like cell culture model using SH-SY5Y cells, ELAVL3 mislocalization occurred weeks before TDP-43 abnormalities were seen. We interrogated genetic databases but did not identify association of ELAVL3 genetic structure associated with ALS. Taken together, these findings suggest that ELAVL3 is an important RBP in ALS pathogenesis acquired early and the neuropathological data suggest it is involved by loss of function rather than cytoplasmic toxicity.

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