The early noncoding region of human papillomavirus type 16 is regulated by cytoplasmic polyadenylation factors

Glahder, Jacob-Andreas Harald; Kristiansen, Karen; Durand, Marjorie; Vinther, Jeppe; Norrild, Bodil

doi:10.1016/j.virusres.2010.02.001

Cited by 5 publications

(5 citation statements)

References 60 publications

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“…GLD2 polyadenylates the 3′-end of mRNAs and specifically elongates AU-rich 3′-UTRs to improve their stability [53]. PAPD4 had higher baseline transcription in FCLs than in muscle, but was significantly changed by RC disease in both tissues ( Fig.…”

Section: Resultsmentioning

confidence: 95%

Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

et al. 2013

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Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5′-UTRs that likely improve translational efficiency, and stabilization of 3′-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD+ redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.

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Section: Resultsmentioning

confidence: 95%

Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

et al. 2013

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“…CPEB1 is the most intensively studied of the four CPEBs, although mainly in neurons and oocytes (reviewed by Richter (11)). Lately, the focus has started turning toward the function of CPEBs in other cells and we have previously shown that CPEB1 can downregulate expression of messengers containing an HPV 3′UTR, while it was expected that CPEB1 would also be changed during HPV‐mediated cancer development (9). Only little is known of the functions of the other CPEB‐like proteins, CPEB2–4.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously found that the most distal part of the E6/E7 messengers from several HPV types has the ability to downregulate protein synthesis of a reporter gene (8). Recently we found that this downregulation in HPV 16 mRNAs is conducted through four cytoplasmic polyadenylation elements (CPEs) situated in the distal part of the E6/E7 messenger, including the 3′UTR (9). The CPE sequence was originally identified in mRNAs from Xenopus oocytes and shown to bind a CPE‐binding protein CPEB (10).…”

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confidence: 99%

Expression of CPEB, GAPDH and U6snRNA in cervical and ovarian tissue during cancer development

Hansen¹,

Ketabi

Rosenstierne

et al. 2009

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Persistent infection with high-risk human papillomavirus (HPV) and expression of the proteins E6 and E7 is a prerequisite for development of cervical cancer. The distal non-coding part of E6/E7 messengers from several HPV types is able to downregulate synthesis of a reporter gene through mechanisms with involvement of cytoplasmic polyadenylation elements (CPEs) in the messengers. We here show that the mRNA levels of one of the four known CPE-binding proteins (CPEBs), the CPEB3, were downregulated in HPV-positive cervical cancers, whereas in ovarian cancer the CPEB1 mRNA level was downregulated. In addition, we showed that the RNA levels of the widely used reference marker GAPDH were upregulated in both cancer forms, and the level of the reference marker U6snRNA was upregulated in cervical cancers. Moreover, a possible correlation between the degree of U6snRNA upregulation and cervical cancer propagation was shown. These changes observed in CPEB1 and CPEB3 might indicate regulatory functions of CPEBs in cancer development of HPV-positive and HPV-negative tumors, respectively, and the U6snRNA, GAPDH mRNA and CPEB1 mRNA levels may be useful as tumor markers for genital cancers although further investigations are needed.

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“…It was previously shown, that the RNA chaperone protein GLD‐3 tether GLD‐2 to target mRNAs in C. elegans (18). In mammalian cells hGLD‐2 interact with hCPEB1 (30, 31). To tether hGLD‐2 to the p53 mRNA, hGLD‐2, either as wild‐type or with a catalytic mutant hGLD‐2 (D215A), was fused to hCPEB1.…”

Section: Resultsmentioning

confidence: 99%

“…This report suggests that CPEB anchors a poly(A) polymerase, Gld4, to the p53 mRNA in human skin fibroblasts. Tethering of Gld‐2 to mRNA on the other hand has been shown to be mediated by Gld‐3 in C. elegans (18), and by hCPEB1 in mammalian cells (30, 31). There might be different levels of regulation between species and possibly between cell‐types as well.…”

Section: Discussionmentioning

confidence: 99%

Involvement of hGLD-2 in cytoplasmic polyadenylation of human p53 mRNA

Glahder

Norrild

2011

Apmis

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Cytoplasmic polyadenylation is a post-transcriptional mechanism regulating mRNA stability and translation. The human p53 3'-untranslated region (3'-UTR) contains two regions similar to cytoplasmic polyadenylation elements (CPEs) just upstream of the poly(A) hexanucleotide. Evaluation of the p53 CPE-like elements was performed by luciferase reporter assays, qPCR, and poly(A) assays. Herein, we report the down regulation of a luciferase reporter fused to the p53 3'-UTR, when human CPE-binding protein 1 (hCPEB1) is overexpressed. This inhibition is partially rescued when hCPEB1fused to hGLD-2 [a human cytoplasmic poly(A) polymerase] is overexpressed instead. The stability of a luciferase mRNA containing the p53 3'-UTR downstream, is decreased when hCPEB1 is overexpressed as seen by qPCR. Expression of hGLD-2 restores the mRNA stability. This is due to elongation of the poly(A) tail as seen by a PCR-based poly(A) test and in vitro poly(A) assay. Taken together, our results suggest that hCPEB1 and hGLD-2 are antagonizing factors regulating p53 mRNA stability.

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The early noncoding region of human papillomavirus type 16 is regulated by cytoplasmic polyadenylation factors

Cited by 5 publications

References 60 publications

Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

Expression of CPEB, GAPDH and U6snRNA in cervical and ovarian tissue during cancer development

Involvement of hGLD-2 in cytoplasmic polyadenylation of human p53 mRNA

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