p53 translational control: A new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics

Halaby, Marie-Jo; Yang, Daping

doi:10.1016/j.gene.2007.01.029

Cited by 72 publications

(79 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2002, a study showed that Mdm2 induces the translation of p53 mRNA from two initiation sites (Yin et al, 2002). Alternative translation initiation at an internal codon is responsible for the generation of the p53/47 isoform, also referred to as DN-p53, D40p53 (Courtois et al, 2004;Scrable et al, 2005;Bourdon, 2007;Halaby and Yang, 2007). Further, Mdm2 selectively targets full-length p53 protein for degradation because the p53/47 isoform lacks the N-terminus Mdm2 binding sites thereby, altering the relative levels of the two-p53 isoforms (Yin et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

View full text Add to dashboard Cite

The tumor suppressor p53 represents a paradigm for gene regulation. Its rapid induction in response to DNA damage conditions has been attributed to both increased half-life of p53 protein and also increased translation of p53 mRNA. Recent advances in our understanding of the post-transcriptional regulation of p53 include the discovery of internal ribosome entry sites (IRESs) within the p53 mRNA. These IRES elements regulate the translation of the full length as well as the N-terminally truncated isoform, p53/47. The p53/47 isoform is generated by alternative initiation at an internal AUG codon present within the p53 ORF. The aim of this review is to summarize the role of translational control mechanisms in regulating p53 functions. We discuss here in detail how diverse cellular stress pathways trigger alterations in the cap-dependent and cap-independent translation of p53 mRNA and how changes in the relative expression levels of p53 isoforms result in more differentiated p53 activity.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

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

“…For example, phosphorylation increases the stability of p53 protein, which reduces the degradation of p53 protein by its negative regulation protein mdm2 and hence results in the elevation of p53 protein level in cells [2,5,6]. Increasing documents have suggested that translational control of p53 mRNA is another crucial reason accounting for the elevation of p53 protein in response to stresses [8,9]. For example, HuR and RPL26 protein have been reported to enhance p53 translation by binding with the 3 0 UTR or 5 0 UTR of p53 mRNA [4,9].…”

Section: Introductionmentioning

confidence: 99%

Zebrafish p53 protein enhances the translation of its own mRNA in response to UV irradiation and CPT treatment

Zhao

Ding

et al. 2012

FEBS Letters

View full text Add to dashboard Cite

Edited by Varda RotterKeywords: p53 Zebrafish RNA binding protein Translational regulation a b s t r a c t p53 protein is an important regulatory factor involved in cell growth and development. In our previous study, we demonstrated that recombined zebrafish p53 protein could specifically bind to its own mRNA in vitro. To determine if a similar interaction exists in zebrafish and if this interaction affects zebrafish development, in the present study, we investigated the interaction of p53 protein and its mRNA in zebrafish embryos. Our results revealed that expressed zebrafish p53 protein could bind with its own mRNA in zebrafish embryos. Furthermore, the endogenous activated or ectopically expressed p53 protein could enhance the relative activity of Renilla luciferase fused with p53 3 0 UTR in response to UV irradiation and CPT treatment, and retarded development of zebrafish embryos was observed.

show abstract

p53 translational control: A new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics

Cited by 72 publications

References 49 publications

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

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

Reversible induction of translational isoforms of p53 in glucose deprivation

Zebrafish p53 protein enhances the translation of its own mRNA in response to UV irradiation and CPT treatment

Contact Info

Product

Resources

About