Internal ribosome entry segment-mediated translation during apoptosis: the role of IRES-trans-acting factors

Spriggs, Keith A.; Bushell, Martin; Mitchell, Sally A.; Willis, Anne E.

doi:10.1038/sj.cdd.4401642

Cited by 150 publications

(154 citation statements)

References 75 publications

Supporting

Mentioning

149

Contrasting

Order By: Relevance

“…Nuclear-cytoplasmic relocalization of ITAFs is essential for cellular IRES function. [58][59][60] We report in the current study a glucose-dependent relocalization of SMAR1, but not PTB, in cultured cells, highlighting the novelty of SMAR1-mediated control in stress. In addition, rescue experiments both ex vivo and in vivo show that the induction of p53 isoform levels on nutrient deprivation is reversible, with these returning to basal levels on nutrient replenishment.…”

Section: Discussionmentioning

confidence: 62%

Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 62%

Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…However, it has not been demonstrated whether hnRNP K binds the LOX mRNA in the nucleus or in the cytoplasm. hnRNP I (PTB) is an IRES trans-acting factor involved in translation regulation of many IRES-containing mRNAs (Valcarcel and Gebauer, 1997;Spriggs et al, 2005;Bushell et al, 2006). Interestingly, it was found that direct protein kinase A phosphorylation of PTB modulates its nucleocytoplasmic distribution (Xie et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Several hnRNPs, including A1, C1/C2, E1/E2, I (PTB), and L, are independently involved in the translational control of specific mRNAs containing internal ribosome entry sites (IRESs) through a capindependent mechanism (for review, see Vagner et al, 2001;Bonnal et al, 2003;Komar and Hatzoglou, 2005). These hnRNP proteins constitute IRES trans-acting factors (ITAFs) that modulate the activity of IRES sequences generally present in the 5Ј untranslated region (UTR) of several viral and cellular mRNAs (Spriggs et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Relocalization of Heterogeneous Nuclear Ribonucleoprotein A1 Controls Translation Initiation of Specific mRNAs

Cammas

Pileur

Bonnal

et al. 2007

MBoC

133

129

View full text Add to dashboard Cite

Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is a nucleocytoplasmic shuttling protein that regulates gene expression through its action on mRNA metabolism and translation. The cytoplasmic redistribution of hnRNP A1 is a regulated process during viral infection and cellular stress. Here, we show that hnRNP A1 is an internal ribosome entry site (IRES) trans-acting factor that binds specifically to the 5 untranslated region of both the human rhinovirus-2 and the human apoptotic peptidase activating factor 1 (apaf-1) mRNAs, thereby regulating their translation. Furthermore, the cytoplasmic redistribution of hnRNP A1 after rhinovirus infection leads to enhanced rhinovirus IRES-mediated translation, whereas the cytoplasmic relocalization of hnRNP A1 after UVC irradiation limits the UVC-triggered translational activation of the apaf-1 IRES. Therefore, this study provides a direct demonstration that IRESs behave as translational enhancer elements regulated by specific trans-acting mRNA binding proteins in given physiological conditions. Our data highlight a new way to regulate protein synthesis in eukaryotes through the subcellular relocalization of a nuclear mRNA-binding protein.

show abstract

“…These are usually comprised of structured regions in the 5 0 untranslated region (UTR) and were initially identified in viruses (Pelletier and Sonenberg, 1988) but have since been reported in eucaryotic mRNAs and are believed to constitute a major form of regulation of protein synthesis in mammalian cells (Johannes and Sarnow, 1998). In particular, IRES seem to play a role under conditions when cap-dependent translation is impaired and eucaryotic IRES-dependent translation activity has been linked to specific conditions in the cell such as the G2 phase of the cell cycle (Pyronnet et al, 2000), apoptosis (Spriggs et al, 2005) or to different stress conditions (reviewed by Holcik and Sonenberg (2005)) to mention some, but also to support specificity of protein synthesis during development (Creancier et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

et al. 2006

View full text Add to dashboard Cite

P53 controls the growth and survival of cells by acting in response to a multitude of cellular stresses. It is, however, not yet fully understood how different p53 activation pathways result in either cell cycle arrest or apoptosis. We and others have described an N-terminally truncated p53 protein (p53/47) originating from a second translation initiation site in the p53 messenger RNA (mRNA), which can interact with p53 and impose altered stability and transactivation properties to p53 complexes. Here we show that cap-dependent and cap-independent mechanisms of initiation govern the translation of the p53 mRNA. Changes in synthesis of full-length p53 or p53/47 are regulated through distinct cell stress-induced pathways acting through separate regions of the p53 mRNA. We also show that some cytotoxic drugs require the presence of full-length p53 to induce apoptosis, whereas for others p53/47 is sufficient. This indicates that by harbouring alternative translation initiation sites, the p53 mRNA gives rise to different levels of the p53 isoforms which help to orchestrate the cell biological outcome of p53 activation in response to different types of cell stress. This sheds new light into the way p53 can integrate and differentiate a large multiplicity of changes in the cellular environment.

show abstract

Internal ribosome entry segment-mediated translation during apoptosis: the role of IRES-trans-acting factors

Cited by 150 publications

References 75 publications

Reversible induction of translational isoforms of p53 in glucose deprivation

Reversible induction of translational isoforms of p53 in glucose deprivation

Cytoplasmic Relocalization of Heterogeneous Nuclear Ribonucleoprotein A1 Controls Translation Initiation of Specific mRNAs

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

Contact Info

Product

Resources

About