Coordinated regulation of p53 apoptotic targets BAX and PUMA by SMAR1 through an identical MAR element

Sinha, Surajit; Malonia, Sunil K.; Mittal, Smriti; Singh, Kamini; Sreenath, Kadreppa; Kamat, Rohan; Mukhopadhyaya, Robin; Pal, Jayanta K.; Chattopadhyay, Samit

doi:10.1038/emboj.2009.395

Cited by 60 publications

(80 citation statements)

References 35 publications

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“…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. Thus glucose deprivation, a form of nutrient-depletion stress, can induce p53 IRESs and also increases cytoplasmic abundance of SMAR1 that in turn binds to p53 IRESs, indicating the role of SMAR1 in controlling translation of p53 isoforms.…”

mentioning

confidence: 70%

“…49 SMAR1 has been implicated in maintaining cellular homeostasis and is a global regulator/modulator of gene expression. 37,38,[50][51][52][53][54] Our recent study showed that SMAR1 is directly linked to translation of both p53 and Δ40p53 in normal as well as glucose-deprived conditions.14-3-3σ was demonstrated as a preferential transcriptional target of Δ40p53. 5,14 The downstream effects of Δ40p53 induction on target gene activation, and the resulting biological outcome, have been previously explored.…”

Section: Discussionmentioning

confidence: 94%

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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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confidence: 70%

Section: Discussionmentioning

confidence: 94%

Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

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“…Severe DNA damage results in sequestration of SMAR1, p53 acetylation and transactivation of Bax and Puma leading to apoptosis. Thus, sequestration of SMAR1 into the PML-NBs acts as a molecular switch to p53-dependent cell arrest and apoptosis in response to DNA damage (Sinha et al, 2010). The mechanisms by which moderate damage resulting from mild stress leads to repair, while severe damage results in the 'decision' to kill a cell, remains unclear.…”

Section: Cell Fate Decisionmentioning

confidence: 99%

“…A mild DNA damage induces SMAR1-generated anti-apoptotic response by promoting p53 deacetylation and specifically repressing Bax and Puma expression. Reducing the expression of SMAR1 by shRNA leads to significant increase in p53-dependent apoptosis (Sinha et al, 2010). Severe DNA damage results in sequestration of SMAR1, p53 acetylation and transactivation of Bax and Puma leading to apoptosis.…”

Section: Cell Fate Decisionmentioning

confidence: 99%

“…First, SMAR1 interacts with p53 and facilitates p53 deacetylation through recruitment of deacetylase HDAC1. Then SMAR1 represses the transcription of Bax and Puma by binding to an identical 25 bp MAR element in their promoters (Sinha et al, 2010). A mild DNA damage induces SMAR1-generated anti-apoptotic response by promoting p53 deacetylation and specifically repressing Bax and Puma expression.…”

Section: Cell Fate Decisionmentioning

confidence: 99%

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Cell Cycle and DNA Damage Response in Postmitotic Neurons

Kruman¹

2011

DNA Repair

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microRNA‐34a aggravates coxsackievirus B3‐induced apoptosis of cardiomyocytes through the SIRT1‐p53 pathway

Jiang

et al. 2019

Journal of Medical Virology

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Viral myocarditis is inflammation of the myocardium mainly caused by a viral infection, and coxsackievirus B3 (CVB3) infection is one of the most common. It is well known that cardiomyocyte apoptosis is involved in the pathogenesis of viral myocarditis. microRNAs (miRNAs, miRs) are endogenous noncoding oligoribonucleotides involved in various pathological conditions, and miR-34a is one of the miRNAs causing apoptosis. Whether miR-34a participates in cardiomyocyte apoptosis during CVB3 infection and the underlying mechanisms is still unclear. In this in vitro study, we found that miR-34a expression increased in cardiomyocytes after CVB3 infection.Furthermore, we found that CVB3 infection augmented histone deacetylase 1 (HDAC1) and Bax expression while inhibiting sirtuin 1 (SIRT1) and Bcl-2 expression, along with the acetylated p53 (Ac-p53) upregulation in cardiomyocytes. The abovementioned phenomenon was reversed by a miR-34a inhibitor after CVB3 infection. In addition, the Ac-p53 amount increased in CVB3-infected cardiomyocytes, and SRT1720 and trichostatin A (TSA) pretreatment decreased Ac-p53 levels. After pifithrin-α pretreatment of CVB3-infected cardiomyocytes, the protein expression level of HDAC1 decreased while that of SIRT1 increased. Moreover, miR-34a expression and CVB3-induced apoptosis of cardiomyocytes were attenuated by pretreatment with SRT1720, TSA, or pifithrin-α, accompanied with Bax downregulation and Bcl-2 upregulation. In summary, these data indicate that miR-34a induces cardiomyocyte apoptosis by downregulating SIRT1, and the activation of the SIRT1-p53 pathway contributes to CVB3-induced apoptosis of cardiomyocytes. Thus, miR-34a might serve as a potential therapeutic target because it promotes cardiomyocyte apoptosis through the SIRT1-p53 signaling pathway.

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Coordinated regulation of p53 apoptotic targets BAX and PUMA by SMAR1 through an identical MAR element

Cited by 60 publications

References 35 publications

Reversible induction of translational isoforms of p53 in glucose deprivation

Reversible induction of translational isoforms of p53 in glucose deprivation

Cell Cycle and DNA Damage Response in Postmitotic Neurons

microRNA‐34a aggravates coxsackievirus B3‐induced apoptosis of cardiomyocytes through the SIRT1‐p53 pathway

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