Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1

Zhang, Min; Zhang, Jin; Chen, Xiangling; Cho, Seong Jun; Chen, Xinbin

doi:10.1101/gad.221739.113

Cited by 52 publications

(68 citation statements)

References 49 publications

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“…Additionally, Rbm38 is found to repress p53 mRNA translation via interaction with eIF4E on p53 mRNA (16). Interestingly, phosphorylation of Rbm38 at serine 195 by GSK3 abolishes its interaction with eIF4E and converts Rbm38 from a repressor to an activator of p53 mRNA translation (17). Furthermore, Rbm38 is found to modulate p53 activity by relieving microRNA-mediated repression of several p53 targets, including p21, DDIT4, LATS2, and Rbm38, itself (18).…”

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confidence: 98%

Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors

Zhang

Ren

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNAbinding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53-dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression.Rbm38 | p53 | aging | hematopoiesis | tumor suppression R NA-binding proteins (RBPs) are master regulators of RNA biogenesis and metabolism (1). Consistent with these crucial functions, RBPs are found to be altered in many human diseases, such as neurological disorders and muscular atrophy (2). Studies also suggest that RBPs form a complex network with oncoproteins and tumor suppressors and thus have profound impacts on tumor development and progression (3, 4).Rbm38, also called RNPC1, encodes an RBP and is expressed as two isoforms, Rbm38 with 239 aa and Rbm38b with 121 aa. Both Rbm38 and Rbm38b contain one RNA recognition motif (RRM), which shares a sequence similarity with the ones found in Musashi, HuR, and nucleolin (5). Rbm38 is known to interact with its target mRNAs and regulate their expression via mRNA stability. For example, Rbm38 is necessary for mRNA stability of p21, p73, GDF15, and HuR transcripts but suppresses mRNA stability of p63 and Mdm2 transcripts (5-10). Rbm38 is also found to regulate alternative splicing of the EPB41 and FGFR2 genes (11,12). Likewise, SUP-12, the Rbm38 ortholog in Caenorhabditis elegans, regulates alternative splicing of the ADF and cofilin genes (13-15). Additionally, Rbm38 is found to repress p53 mRNA translation via interaction with eIF4E on p53 mRNA (16). Interestingly, phosphorylation of Rbm38 at serine 195 by GSK3 abolishes its interaction with eIF4E and converts Rbm38 from a repressor to an activator of p53 mRNA translation (17). Furthermore, Rbm38 is found to modulate p53 activity by relieving microRNA-mediated repression of several p53 targets, including p21, DDIT4, LATS2, and Rbm38, itself (18).The biological function of Rbm38 is implicated in the cell cycle control, differentiation, and senescence (5, 16, 19). Consistently, altered expression of Rbm38 is found in many types of cancers. For example, Rbm38 overexpression is found in bre...

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confidence: 98%

Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors

Zhang

Ren

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…p53 mRNA (42,60,65,67). In addition, p53 turnover can be reduced by several mechanisms that decrease expression or activity of Mdm2 and related E3 ubiquitin ligases (33,44,53).…”

Section: Tekt1mentioning

confidence: 99%

p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization

Fox

Ebert

Bongers

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

101

130

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Fox DK, Ebert SM, Bongers KS, Dyle MC, Bullard SA, Dierdorff JM, Kunkel SD, Adams CM. p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization. Am J Physiol Endocrinol Metab 307: E245-E261, 2014. First published June 3, 2014; doi:10.1152/ajpendo.00010.2014.-Immobilization causes skeletal muscle atrophy via complex signaling pathways that are not well understood. To better understand these pathways, we investigated the roles of p53 and ATF4, two transcription factors that mediate adaptations to a variety of cellular stresses. Using mouse models, we demonstrate that 3 days of muscle immobilization induces muscle atrophy and increases expression of p53 and ATF4. Furthermore, muscle fibers lacking p53 or ATF4 are partially resistant to immobilization-induced muscle atrophy, and forced expression of p53 or ATF4 induces muscle fiber atrophy in the absence of immobilization. Importantly, however, p53 and ATF4 do not require each other to promote atrophy, and coexpression of p53 and ATF4 induces more atrophy than either transcription factor alone. Moreover, muscle fibers lacking both p53 and ATF4 are more resistant to immobilization-induced atrophy than fibers lacking only p53 or ATF4. Interestingly, the independent and additive nature of the p53 and ATF4 pathways allows for combinatorial control of at least one downstream effector, p21. Using genome-wide mRNA expression arrays, we identified p21 mRNA as a skeletal muscle transcript that is highly induced in immobilized muscle via the combined actions of p53 and ATF4. Additionally, in mouse muscle, p21 induces atrophy in a manner that does not require immobilization, p53 or ATF4, and p21 is required for atrophy induced by immobilization, p53, and ATF4. Collectively, these results identify p53 and ATF4 as essential and complementary mediators of immobilization-induced muscle atrophy and discover p21 as a critical downstream effector of the p53 and ATF4 pathways.

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“…15 Apart from various ITAFs, p53 5'UTR is also known to bind several proteins such as RPL26, 16 nucleolin, 17 PDCD4 18 and RNPC1. 19 Nutrient-limitation or starvation is also known to induce cellular stress. In Drosophila under poor nutritional conditions, FOXO (a Forkhead-box transcription factor) mediates accumulation of INR via IRES-mediated translation of the INR mRNA.…”

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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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Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1

Cited by 52 publications

References 49 publications

Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors

Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors

p53 and ATF4 mediate distinct and additive pathways to skeletal muscle atrophy during limb immobilization

Reversible induction of translational isoforms of p53 in glucose deprivation

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