hnRNP Q regulates translation of p53 in normal and stress conditions

Kim, Doyoung; Kim, W; Kh, Lee; Sh, Kim; Lee, Hye Rin; Kim, Hyung Jun; Jung, Yongsik; Jh, Choi; Kt, Kim

doi:10.1038/cdd.2012.109

Cited by 51 publications

(61 citation statements)

References 40 publications

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“…It was recently found that mouse p53 mRNA also contains an IRES sequence (14), which is consistent with a previous finding that mouse p53 synthesis is upregulated by DNA damage (5). The increase in p53 IRES activity following different cellular stress has been observed by a number of recent reports (15)(16)(17)(18)(19)(20).…”

supporting

confidence: 88%

Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage

Halaby

Harris

Miskimins

et al. 2015

Molecular and Cellular Biology

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Synthesis of the p53 tumor suppressor and its subsequent activation following DNA damage are critical for its protection against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) at the 5= untranslated region of the p53 mRNA. However, the connection between IRES-mediated p53 translation and p53's tumor suppressive function is unknown. In this study, we identified two p53 IRES trans-acting factors, translational control protein 80 (TCP80), and RNA helicase A (RHA), which positively regulate p53 IRES activity. Overexpression of TCP80 and RHA also leads to increased expression and synthesis of p53. Furthermore, we discovered two breast cancer cell lines that retain wild-type p53 but exhibit defective p53 induction and synthesis following DNA damage. The levels of TCP80 and RHA are extremely low in both cell lines, and expression of both proteins is required to significantly increase the p53 IRES activity in these cells. Moreover, we found cancer cells transfected with a shRNA against TCP80 not only exhibit decreased expression of TCP80 and RHA but also display defective p53 induction and diminished ability to induce senescence following DNA damage. Therefore, our findings reveal a novel mechanism of p53 inactivation that links deregulation of IRES-mediated p53 translation with tumorigenesis.O ne of the most important tumor suppressors identified thus far is p53. Under normal conditions, p53 is inactive, and its cellular levels are low. In response to various genotoxic or cytotoxic stress, including DNA damage, p53 becomes activated (1). The activated p53 causes cell growth arrest or apoptosis, allowing damaged cells to self-repair or be eliminated. In this manner, p53 protects against malignant transformation of normal cells (2, 3). Activation of p53 involves both accumulation and posttranslational modification. It is thought that the control of p53 induction or accumulation occurs mainly at the translational and posttranslational levels (1). Although levels of p53 are known to be regulated by the ubiquitin ligase mouse double minute 2 (MDM2), now there is clear evidence showing that enhanced p53 translation is essential for its induction following DNA damage (4). More specifically, the 5= untranslated region (5= UTR) of p53 mRNA was found to be a major site for regulation of p53 translation (5, 6). The mechanism underlying translational regulation of p53 induction via its 5= UTR has started to emerge.Cap-dependent initiation of protein translation is used by the majority of mRNAs, since almost all eukaryotic mRNAs have an N 7 -methylguanosine cap structure at their 5= ends. Eukaryotic translation initiation factor 4E (eIF-4E), a translation initiation protein that binds to the cap structure, initiates the process (7). In situations where cap-dependent translation is impaired, including apoptosis or DNA damage, cap-independent protein translation, mediated by an internal ribosomal entry site (IRES) that does not require the participation of eIF-4E, is needed in eukaryotes for the synthe...

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supporting

confidence: 88%

Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage

Halaby

Harris

Miskimins

et al. 2015

Molecular and Cellular Biology

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“…14 hnRNPQ was demonstrated to bind to p53 5'UTR and control its translation efficiency. 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.…”

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confidence: 99%

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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“…Endogenous hCdc73 protein was specifically precipitated with the biotinylated p53 mRNA, because no binding occurred when excess non-biotinylated p53 mRNA was used as a competitor. A heterogeneous nuclear ribonucleoprotein Q, a known p53 mRNA-binding protein, was used as a positive control 28 . We then examined the region of p53 mRNA that hCdc73 binds.…”

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confidence: 99%

Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis

Chung

Youn

et al. 2014

Nat Commun

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The parafibromin/hCdc73 is a component of the PAFc, which controls RNA polymerase II-mediated general transcription. In parathyroid carcinoma and familial autosomal dominant hyperparathyroidism-jaw tumour (HPT-JT), hCdc73 mutations are heavily implicated, yet the underlying mechanism of its carcinogenic action is poorly understood. Here we demonstrate that hCdc73 specifically controls messenger RNA stability of p53 and p53-mediated apoptosis. hCdc73 is associated with mature p53 mRNA in the cytoplasm and facilitates its degradation. Cytoplasmic hCdc73 physically interacts with eEF1Bg and hSki8, and this interaction is required to bind and destabilize p53 mRNA. Furthermore, enhanced association of p53 mRNA with a cancer-driven hCdc73(K34Q) mutant was also observed. As a result, reduced p53 expression as well as enhanced cell proliferation was acquired in the hCdc73 (K34Q)-overexpressed cells. Altogether, our findings indicate that hCdc73 directly targets p53 mRNA to repress p53 expression, and aberrant regulation of this interaction may lead to tumour progression.

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hnRNP Q regulates translation of p53 in normal and stress conditions

Cited by 51 publications

References 40 publications

Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage

Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage

Reversible induction of translational isoforms of p53 in glucose deprivation

Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis

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