<scp>IRES</scp> mediated translational regulation of p53 isoforms

Arandkar, Sharathchandra; Katoch, Aanchal

doi:10.1002/wrna.1202

Cited by 34 publications

(39 citation statements)

References 75 publications

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“…Some of the well-characterized ITAFs are human antigen R (HuR), La autoantigen, programed cell death 4 (PDCD4), polypyrimidine tract binding (PTB) protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), hnRNAC1/C2 upstream of NRAS (UnR), nuclear factor 45 (NF45), insulinlike growth factor 2-binding protein 1 (IGF2BP1), Y-box protein 1 (YB1), and poly(C) binding protein (PCBP) [20,49,50]. The levels, activity, and localization of these ITAFs are regulated by various signaling pathways, which in turn regulate the IRES-mediated translation.…”

Section: Ires Trans-acting Factors Regulating Ires-mediated Translationmentioning

confidence: 99%

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Sharma

Bressler

Patel

et al. 2016

Journal of Nucleic Acids

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Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

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Section: Ires Trans-acting Factors Regulating Ires-mediated Translationmentioning

confidence: 99%

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Sharma

Bressler

Patel

et al. 2016

Journal of Nucleic Acids

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“…The D133TP53 transcript also encodes the D160p53 protein, which lacks the first 160 amino acids generated by alternative initiation of translation (10). In addition, internal ribosome entry site (IRES)-mediated translation of TP53 mRNA leads to expression of the D40p53 isoforms (35). Of note, there are two sets of transcripts capable of encoding both full-length (FL)/D40TP53_T1 and FL/D40TP53_T2, differ by only three nucleotides in their length, due to the incorporation of CAG at the intron exon junction of exon 2 (Fig.…”

Section: Introductionmentioning

confidence: 99%

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

et al. 2016

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TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53a_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCRbased methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151-9. Ó2016 AACR.

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“…Translation of cellular mRNA can likewise be mediated via initiation at cellular IRESs during many physiological and pathological stress conditions, as exemplified by p53 IRESs (Graber & Holcik, 2007;Komar & Hatzoglou, 2011;Sharathchandra et al, 2014) used in this study (Figs 5 and 6). RNA structures and canonical initiation factors/ITAFs involved in IRES-driven translation initiation appear to vary for IRESs in cellular and viral mRNA (Komar & Hatzoglou, 2011;Niepmann, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…We also investigated whether IDR can inhibit the cellular IRES-mediated translation. Two cellular p53 IRESs, IRES (1 and 2) and IRES (2), were shown to regulate the translation of full-length p53 and a truncated isoform p53, respectively (Graber & Holcik, 2007;Sharathchandra et al, 2014). Therefore, a dicistronic reporter construct with p53 IRES (1 and 2) was also generated.…”

Section: Mechanism-of-action Of Idrmentioning

confidence: 99%

Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site

Hou¹,

Lü

Wu³

et al. 2016

Journal of General Virology

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Enterovirus 71 (EV71) causes life-threatening diseases with neurological manifestations in young children. However, the treatment of EV71 infections remains an unmet medical need. Idarubicin (IDR) is an anthracycline compound that is used therapeutically for certain types of tumour. In this study, we identified IDR as an EV71 inhibitor, which displayed antiviral potency in the submicromolar range and substantially protected cells from the cytopathic effects and cell death caused by EV71 infections. The antiviral effects extended to several other enterovirus (EV) species, and these effects were independent of cytotoxicity or topoisomerase inhibition. Structure-activity relationship studies indicated the importance of the anthracycline scaffold for anti-EV potency. IDR effectively blocked the synthesis of viral protein and RNA, but not the viral proteolysis processes. Moreover, anthracyclines were demonstrated to suppress EV internal ribosomal entry site (IRES)-mediated translation; conversely, the cellular p53 IRES activity was not sensitive to IDR action. Inhibition of IRES-mediated translation by IDR correlated with the affinity of binding between IDR and the particular IRES. Moreover, IDR impaired binding between the EV71 IRES RNA and hnRNP A1, a known host IRES trans-acting factor. In sum, we have identified a USA FDA-approved anticancer drug with the new indication as a selective EV IRES binder and inhibitor. The finding may also provide leads for the development of novel antiviral therapies directed at the EV IRES RNA.

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IRES mediated translational regulation of p53 isoforms

Cited by 34 publications

References 75 publications

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology

Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site

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