Tumor Suppressor SMAR1 Activates and Stabilizes p53 through Its Arginine-Serine-rich Motif

Jalota, Archana; Singh, Kamini; Pavithra, Lakshminarasimhan; Kaul-Ghanekar, Ruchika; Jameel, Shahid; Chattopadhyay, Samit

doi:10.1074/jbc.m413200200

Cited by 34 publications

(46 citation statements)

References 47 publications

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“…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%

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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Section: Discussionmentioning

confidence: 94%

Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

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“…It was finally probed with the following antibodies: anti-p53 (DO-1); anti-phospho-p53 Ser-15, and anti-pCdc-2. The detailed protocol for the same is discussed in our earlier publication (30).…”

Section: Methodsmentioning

confidence: 99%

“…for Cell Cycle Regulation-Earlier, we have reported that SMAR1 interacts with p53 and modulates its function (29,30). To delineate the minimal domain of SMAR1 that interacts with and activates p53, several truncations of SMAR1 were performed (30).…”

Section: Smar1-(288 -350) Arginine-serine-rich Motif Responsiblementioning

confidence: 99%

“…To delineate the minimal domain of SMAR1 that interacts with and activates p53, several truncations of SMAR1 were performed (30). SMAR1 is a 548-aa protein that is alternatively spliced, resulting in a deletion of 39 aa at its N terminus (33).…”

Section: Smar1-(288 -350) Arginine-serine-rich Motif Responsiblementioning

confidence: 99%

“…SMAR1 (Scaffold Matrix Attachment Region binding protein 1), a 68-kDa protein, has been shown previously to interact with p53 and to regulate the cell cycle (29). It has been further reported that the arginine-serine-rich domain (RS domain) of SMAR1, upon phosphorylation by the PKC family of proteins, phosphorylates p53 specifically at its serine 15 residue (30). The minimal domain of SMAR1 required for its interaction with p53 resides within the 160 -350-aa region.…”

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SMAR1-derived P44 Peptide Retains Its Tumor Suppressor Function through Modulation of p53

Jalota‐Badhwar

Kaul-Ghanekar

Mogare

et al. 2007

Journal of Biological Chemistry

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The use of pharmacologically active short peptide sequences is a better option in cancer therapeutics than the full-length protein. Here we report one such 44-mer peptide sequence of SMAR1 (TAT-SMAR1 wild type, P44) that retains the tumor suppressor activity of the full-length protein. The protein transduction domain of human immunodeficiency virus, type 1, Tat protein was used here to deliver the 33-mer peptide of SMAR1 into the cells. P44 peptide could efficiently activate p53 by mediating its phosphorylation at serine 15, resulting in the activation of p21 and in effect regulating cell cycle checkpoint. In vitro phosphorylation assays with point-mutated P44-derived peptides suggested that serine 347 of SMAR1 was indispensable for its activity and represented the substrate motif for the protein kinase C family of proteins. Using xenograft nude mice models, we further demonstrate that P44 was capable of inhibiting tumor growth by preventing cellular proliferation. P44 treatment to tumor-bearing mice prevented the formation of poorly organized tumor vasculature and an increase in hypoxia-inducible factor-1␣ expression, both being signatures of tumor progression. The chimeric TAT-SMAR1-derived peptide, P44, thus has a strong therapeutic potential as an anticancer drug.

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A mini review of MAR-binding proteins

et al. 2010

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Genomic DNA encompasses several levels of organization, the nuclear matrix mediates the formation of DNA loop domains that are anchored to matrix attachment regions (MARs). By means of specific interaction with MAR binding proteins (MARBPs), MAR plays an important regulation role in enhancing transgene expression, decreasing expression variation among individuals of different transformants and serving as the replication origin. Through these years, some MARBPs have been identified and characterized from humans, plants, animals and algae so far and the list is growing. Most of MARBPs exist in a co-repressor/co-activator complex and involve in chromosome folding, regulation of gene expression, influencing cell development and inducing cell apoptosis. This review covers recent advances that have contributed to our understanding of MARBPs.

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Tumor Suppressor SMAR1 Activates and Stabilizes p53 through Its Arginine-Serine-rich Motif

Cited by 34 publications

References 47 publications

Reversible induction of translational isoforms of p53 in glucose deprivation

Reversible induction of translational isoforms of p53 in glucose deprivation

SMAR1-derived P44 Peptide Retains Its Tumor Suppressor Function through Modulation of p53

A mini review of MAR-binding proteins

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