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Fåhraeus, Robin
Publications (10 of 23) Show all publications
diva2:1323475
Open this publication in new window or tab >>A single synonymous mutation determines the phosphorylation and stability of the nascent protein
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2019 (English)In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 11, no 3, p. 187-199Article in journal (Refereed) Published
Abstract [en]

p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
synonymous mutations, intrinsically disordered proteins, cell signaling, MDM2, p53 messenger RNA, ATM kinase
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-159634 (URN)10.1093/jmcb/mjy049 (DOI)000467903600002 ()30252118 (PubMedID)
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-06-12Bibliographically approved
Gu, X., Wang, L., Boldrup, L., Coates, P. J., Fåhraeus, R., Sgaramella, N., . . . Nylander, K. (2019). AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck. Cancers, 11(3), Article ID 347.
Open this publication in new window or tab >>AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 3, article id 347Article in journal (Refereed) Published
Abstract [en]

A growing number of long non-coding RNAs (lncRNAs) have been linked to squamous cell carcinoma of the head and neck (SCCHN). A subclass of lncRNAs, termed enhancer RNAs (eRNAs), are derived from enhancer regions and could contribute to enhancer function. In this study, we developed an integrated data analysis approach to identify key eRNAs in SCCHN. Tissue-specific enhancer-derived RNAs and their regulated genes previously predicted using the computational pipeline PreSTIGE, were considered as putative eRNA-target pairs. The interactive web servers, TANRIC (the Atlas of Noncoding RNAs in Cancer) and cBioPortal, were used to explore the RNA levels and clinical data from the Cancer Genome Atlas (TCGA) project. Requiring that key eRNAs should show significant associations with overall survival (Kaplan-Meier log-rank test, p < 0.05) and the predicted target (correlation coefficient r > 0.4, p < 0.001), we identified five key eRNA candidates. The most significant survival-associated eRNA was AP001056.1 with ICOSLG encoding an immune checkpoint protein as its regulated target. Another 1640 genes also showed significant correlation with AP001056.1 (r > 0.4, p < 0.001), with the "immune system process" being the most significantly enriched biological process (adjusted p < 0.001). Our results suggest that AP001056.1 is a key immune-related eRNA in SCCHN with a positive impact on clinical outcome.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
AP001056.1, lncRNA, enhancer, SCCHN, ICOSLG, tumor immunity
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-159881 (URN)10.3390/cancers11030347 (DOI)000468550200077 ()30862109 (PubMedID)
Funder
Swedish Cancer Society, 18 05 42Swedish Cancer Society, 18 02 96Västerbotten County Council
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Gu, X., Coates, P. J., Boldrup, L., Wang, L., Krejci, A., Hupp, T., . . . Nylander, K. (2019). Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue. Journal of Oral Pathology & Medicine, 48(1), 24-30
Open this publication in new window or tab >>Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue
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2019 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 48, no 1, p. 24-30Article in journal (Refereed) Published
Abstract [en]

Background The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment. Materials and methods To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (<= 40 years) and five elderly patients (>= 50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes. Results In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044). Conclusions Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
age, copy number variation, prognosis, squamous cell carcinoma of the oral tongue, whole-exome sequencing
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155648 (URN)10.1111/jop.12792 (DOI)000454799800005 ()30357923 (PubMedID)
Funder
Swedish Cancer Society, 17 0663Västerbotten County Council
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved
Martins, R. P., Malbert-Colas, L., Lista, M. J., Daskalogianni, C., Apcher, S., Pla, M., . . . Fåhraeus, R. (2019). Nuclear processing of nascent transcripts determines synthesis of full-length proteins and antigenic peptides. Nucleic Acids Research, 47(6), 3086-3100
Open this publication in new window or tab >>Nuclear processing of nascent transcripts determines synthesis of full-length proteins and antigenic peptides
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2019 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 6, p. 3086-3100Article in journal (Refereed) Published
Abstract [en]

Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-159621 (URN)10.1093/nar/gky1296 (DOI)000467964800033 ()30624716 (PubMedID)
Available from: 2019-06-13 Created: 2019-06-13 Last updated: 2019-06-13Bibliographically approved
Karakostis, K. & Fåhraeus, R. (2019). Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures. BMC Cancer, 19(1), Article ID 915.
Open this publication in new window or tab >>Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures
2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, no 1, article id 915Article, review/survey (Refereed) Published
Abstract [en]

Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein - RNA and protein - protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of the p53 mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein - protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
RNA world, Ciona intestinalis, Transcription factor, Intrinsically disordered proteins, Protein-RNA interactions, mRNA translation, Molecular basis of disease
National Category
Cancer and Oncology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-164405 (URN)10.1186/s12885-019-6118-y (DOI)000485960000002 ()31519161 (PubMedID)
Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2019-11-05Bibliographically approved
Haronikova, L., Olivares-Illana, V., Wang, L., Karakostis, K., Chen, S. & Fåhraeus, R. (2019). The p53 mRNA: an integral part of the cellular stress response. Nucleic Acids Research, 47(7), 3257-3271
Open this publication in new window or tab >>The p53 mRNA: an integral part of the cellular stress response
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2019 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 7, p. 3257-3271Article in journal (Refereed) Published
Abstract [en]

A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-159620 (URN)10.1093/nar/gkz124 (DOI)000467965900007 ()30828720 (PubMedID)
Available from: 2019-06-13 Created: 2019-06-13 Last updated: 2019-06-13Bibliographically approved
Sgaramella, N., Wilms, T., Boldrup, L., Loljung, L., Gu, X., Coates, P. J., . . . Nylander, K. (2018). Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue. Oncology Letters, 16(5), 6603-6607
Open this publication in new window or tab >>Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue
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2018 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 16, no 5, p. 6603-6607Article in journal (Refereed) Published
Abstract [en]

The oral tongue is the most common site for tumours within the oral cavity. Despite intense research, there has been no improvement in the survival rate for patients with oral tongue squamous cell carcinoma (OTSCC) during the last decades. Differences between oral cancer patients based on ethno-geographical distribution have been reported. The present study used immunohistochemistry to evaluate commonly used markers of cancer cell phenotypes, E-cadherin, -catenin and cytokeratins 5 and 19, in 120 patients with OTSCC. To evaluate the impact of ethnicity, patients from Sweden and Italy were included. A higher proportion of Swedish patients exhibited high expression of E-cadherin in their tumours (P=0.039), and high levels of E-cadherin in Swedish OTSCC patients that had succumbed to their disease were associated with poor prognosis. These data demonstrated differences in the pathological characteristics of OTSCC between two different European populations. The findings emphasise the need to take ethnicity/geographical location of patients into account when comparing results from different studies of OTSCC.

Place, publisher, year, edition, pages
Spandidos Publications, 2018
Keywords
E-cadherin, beta catenin, squamous cell carcinoma, oral tongue, ethnicity
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-153550 (URN)10.3892/ol.2018.9452 (DOI)000448433500141 ()30405799 (PubMedID)
Funder
Swedish Cancer Society, 17 06 63Västerbotten County Council, MEYS-NPSI-LO1413
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-05-10Bibliographically approved
diva2:1282590
Open this publication in new window or tab >>In Cellulo Protein-mRNA Interaction Assay to Determine the Action of G-Quadruplex-Binding Molecules
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2018 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 12, article id 3124Article in journal (Refereed) Published
Abstract [en]

Protein-RNA interactions (PRIs) control pivotal steps in RNA biogenesis, regulate multiple physiological and pathological cellular networks, and are emerging as important drug targets. However, targeting of specific protein-RNA interactions for therapeutic developments is still poorly advanced. Studies and manipulation of these interactions are technically challenging and in vitro drug screening assays are often hampered due to the complexity of RNA structures. The binding of nucleolin (NCL) to a G-quadruplex (G4) structure in the messenger RNA (mRNA) of the Epstein-Barr virus (EBV)-encoded EBNA1 has emerged as an interesting therapeutic target to interfere with immune evasion of EBV-associated cancers. Using the NCL-EBNA1 mRNA interaction as a model, we describe a quantitative proximity ligation assay (PLA)-based in cellulo approach to determine the structure activity relationship of small chemical G4 ligands. Our results show how different G4 ligands have different effects on NCL binding to G4 of the EBNA1 mRNA and highlight the importance of in-cellulo screening assays for targeting RNA structure-dependent interactions.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
structure-activity relationship, protein-mRNA interactions, G-quadruplexes, PhenDC3, pyridostatin, EBNA1, Epstein-Barr virus (EBV)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-155652 (URN)10.3390/molecules23123124 (DOI)000454523000074 ()30501034 (PubMedID)
Funder
Swedish Cancer Society, 16059Swedish Research Council
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-05-10Bibliographically approved
Sgaramella, N., Gu, X., Boldrup, L., Coates, P. J., Fåhraeus, R., Califano, L., . . . Nylander, K. (2018). Searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck, with specific focus on tumours of the tongue. Current Topics in Medicinal Chemistry, 18(3), 214-218
Open this publication in new window or tab >>Searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck, with specific focus on tumours of the tongue
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2018 (English)In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 18, no 3, p. 214-218Article, review/survey (Refereed) Published
Abstract [en]

Squamous cell carcinoma of the head and neck, SCCHN, is a heterogeneous group of tumours not only concerning the site of origin but also regarding aetiology. The 5-year survival for the whole group of SCCHN tumours has not significantly improved over the last 20-25 years. Apart from tumour spread to lymph nodes, N status, gains and losses of specific chromosomes are the only factors shown to be independent prognostic markers for these tumours. Worldwide, an increasing number of people ≤ 40 years are seen being affected by tongue SCC, the most common tumour within the SCCHN group. Even without any clinical signs of metastasis, up to 30% of all tongue SCC have histologically detectable spread to lymph nodes. In this mini review, field cancerization, tumour microenvironment, the so called EMT (epithelial mesenchymal transition) process and the role of viruses in development of SCCHN are discussed as well as potential new therapeutic targets. For the group of tongue SCC, with the increasing incidence seen in young patients and particularly women, new data with impact on prognosis and treatment are urgently needed. But as long as data from the analyses of several sub sites are presented as valid for the whole group of tumours, this vital point is missed.

Place, publisher, year, edition, pages
Bentham Science Publishers, 2018
Keywords
squamous cell carcinoma, tongue, prognosis, therapy, miRNA, HPV, EBV, p63
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-148841 (URN)10.2174/1568026618666180116121624 (DOI)000432250800006 ()29345578 (PubMedID)
Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2019-05-10Bibliographically approved
Gnanasundram, S. V. & Fåhraeus, R. (2018). Translation Stress Regulates Ribosome Synthesis and Cell Proliferation. International Journal of Molecular Sciences, 19(12), Article ID 3757.
Open this publication in new window or tab >>Translation Stress Regulates Ribosome Synthesis and Cell Proliferation
2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 12, article id 3757Article, review/survey (Refereed) Published
Abstract [en]

Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3K delta-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
mRNA translation stress, ribosome biogenesis, oncogene, cell cycle, cell signaling pathway
National Category
Cell Biology Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-155978 (URN)10.3390/ijms19123757 (DOI)000455323500059 ()30486342 (PubMedID)
Funder
Swedish Cancer Society, 160598Swedish Research Council
Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2019-05-10Bibliographically approved
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