p53 and little brother p53/47: linking IRES activities with protein functions

Grover, Richa; Candeias, Marco M.; Fåhræus, Robin; Das, Saumitra

doi:10.1038/onc.2009.138

Cited by 46 publications

(55 citation statements)

References 55 publications

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“…The level of p53 protein is indicative of the cellular response to stressors [Vogelstein et al 2000]. The transcriptional and translational activation of the p53 protein after exposure to genotoxic and nongenotoxic stressors induces the expression of proteins involved in redox regulation, cell-cycle arrest, DNA repair, protein degradation, and apoptosis [El-Deiry et al 1993;Erster et al 2004;Grover et al 2009;Halaby and Yang 2007]. The p53 protein's apoptotic function is primarily, but not exclusively, mediated via activation of mitochondrial apoptotic machinery through the intrinsic pathway [Erster et al 2004;Grover et al 2009;Hamel et al 1996;Miyashita and Reed 1995].…”

Section: Introductionmentioning

confidence: 99%

Effects of Estrogen Metabolite 2-Methoxyestradiol on Tumor Suppressor Protein p53 and Proliferation of Breast Cancer Cells

Siebert¹,

Sanchez²,

Dinda

et al. 2011

Systems Biology in Reproductive Medicine

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Section: Introductionmentioning

confidence: 99%

Effects of Estrogen Metabolite 2-Methoxyestradiol on Tumor Suppressor Protein p53 and Proliferation of Breast Cancer Cells

Siebert¹,

Sanchez²,

Dinda

et al. 2011

Systems Biology in Reproductive Medicine

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“…Insertion of an open-reading frame followed by a hairpin structure in the 5 0 -untranslated region of p53 resulted in an increase in p53/47 synthesis and a decrease in p53, indicating that cap-independent mechanisms of initiation control p53/47 translation via an internal ribosome entry site (IRES) structure located in the region of þ 1 to þ 120 of p53. Hence, the coding region of p53 serves as IRES for p53/47 (Candeias et al, 2006;Ray et al, 2006;Grover et al, 2009). It has also been shown that p53/47 could be generated by alternative splicing (Ghosh et al, 2004), but it should be a rare event as the full-length p53 mRNA was evident after 20 quantitative PCR cycles, whereas the p53/47 message required 40 quantitative PCR cycles, which represents approximately 2 Â 10 20 times less amount of p53/47 mRNA.…”

Section: Introductionmentioning

confidence: 99%

p53 isoforms gain functions

Olivares‐Illana

Fåhræus

2010

Oncogene

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Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis. One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response. It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions. The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest. On the other hand, p53 itself induces G1 arrest and has no effect on the G2. The two isoforms D133p53, which lacks the first 133 amino acids, and p53b, which carries an alternative C-terminus, are derived from alternative promoter usage or splicing, respectively, and are together implied in controlling cellular senescence. Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses. This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains.

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“…Interestingly, MDM2 has also been shown to interact with coding sequence of the IRES in p53 mRNA. 12,35,36 A recent work suggested stress-dependent formation of a ternary complex of three proteins: p53, MDM2 and SMAR1, 37 another transcriptional target of p53 that can modulate p53 transactivation potential. 37,38 We now find that SMAR1, a predominantly nuclear protein becomes abundant in the cytoplasm under glucose deprivation.…”

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Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

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Tumor suppressor protein p53 is a master transcription regulator, indispensable for controlling several cellular pathways. Earlier work in our laboratory led to the identification of dual internal ribosome entry site (IRES) structure of p53 mRNA that regulates translation of full-length p53 and Δ40p53. IRES-mediated translation of both isoforms is enhanced under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum stress, oncogene-induced senescence and cancer. In this study, we addressed nutrient-mediated translational regulation of p53 mRNA using glucose depletion. In cell lines, this nutrient-depletion stress relatively induced p53 IRES activities from bicistronic reporter constructs with concomitant increase in levels of p53 isoforms. Surprisingly, we found scaffold/matrix attachment region-binding protein 1 (SMAR1), a predominantly nuclear protein is abundant in the cytoplasm under glucose deprivation. Importantly under these conditions polypyrimidine-tractbinding protein, an established p53 ITAF did not show nuclear-cytoplasmic relocalization highlighting the novelty of SMAR1-mediated control in stress. In vivo studies in mice revealed starvation-induced increase in SMAR1, p53 and Δ40p53 levels that was reversible on dietary replenishment. SMAR1 associated with p53 IRES sequences ex vivo, with an increase in interaction on glucose starvation. RNAi-mediated-transient SMAR1 knockdown decreased p53 IRES activities in normal conditions and under glucose deprivation, this being reflected in changes in mRNAs in the p53 and Δ40p53 target genes involved in cell-cycle arrest, metabolism and apoptosis such as p21, TIGAR and Bax. This study provides a new physiological insight into the regulation of this critical tumor suppressor in nutrient starvation, also suggesting important functions of the p53 isoforms in these conditions as evident from the downstream transcriptional target activation. Cell Death and Differentiation (2015) 22, 1203-1218; doi:10.1038/cdd.2014.220; published online 27 February 2015 p53 is a master transcription factor and tumor suppressor. Apart from post-translational modifications of p53 and concomitant protein-protein interactions of p53 with diverse factors, translational control of p53 mRNA also plays an important role under stress conditions. 1 p53 and its N-terminally truncated isoform Δ40p53 (also known as ΔN-p53 or p53/47) are translated by internal ribosome entry site (IRES)-mediated translation initiation from the same mRNA under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum (ER) stress, oncogene-induced senescence and cancer. [2][3][4][5][6][7] Thus, p53 mRNA has a dual IRES structure. 8 For their function, these IRESs rely on IRES trans-acting factors (ITAFs). Polypyrimidine-tract-binding protein (PTB) was shown to have differential affinity for the two IRESs of p53 and regulated p53 IRES functions by translocating from nucleus to cytoplasm on doxorubicin-induced DNA damage. 3 This PTB-med...

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p53 and little brother p53/47: linking IRES activities with protein functions

Cited by 46 publications

References 55 publications

Effects of Estrogen Metabolite 2-Methoxyestradiol on Tumor Suppressor Protein p53 and Proliferation of Breast Cancer Cells

Effects of Estrogen Metabolite 2-Methoxyestradiol on Tumor Suppressor Protein p53 and Proliferation of Breast Cancer Cells

p53 isoforms gain functions

Reversible induction of translational isoforms of p53 in glucose deprivation

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