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...

Cycloxygenase-2 (COX-2) is the inducible isoform of cycloxygenase enzyme family that catalyzes synthesis of inflammatory mediators, prostanoids and prostaglandins, and therefore, can be targeted by anti-inflammatory drugs. Here, we showed a plant polyphenol, kaempferol, attenuated IL-6-induced COX-2 expression in human monocytic THP-1 cells suggesting its beneficial role in chronic inflammation. Kaempferol deactivated and prevented nuclear localization of two major transcription factors STAT3 and NF-κB, mutually responsible for COX-2 induction in response to IL-6. Moreover, STAT3 and NF-κB were simultaneously deactivated by kaempferol in acute inflammation, as shown by carrageenan-induced mouse paw edema model. The concomitant reduction in COX-2 expression in paw tissues suggested kaempferol’s role in mitigation of inflammation by targeting STAT3 and NF-κB.

Cardiovascular diseases (CVDs) are the commonest cause of global mortality and morbidity. Atherosclerosis, the fundamental pathological manifestation of CVDs, is a complex process and is poorly managed both in terms of preventive and therapeutic intervention. Aberrant lipid metabolism and chronic inflammation play critical roles in the development of atherosclerosis. These processes can be targeted for effective management of the disease. Although managing lipid metabolism is in the forefront of current therapeutic approaches, controlling inflammation may also prove to be crucial for an efficient treatment regimen of the disease. Flavonoids, the plant-derived polyphenols, are known for their antiinflammatory properties. This review discusses the possible antiatherogenic role of 3 flavonoids, namely, chrysin, quercetin, and luteolin primarily known for their antiinflammatory properties.

This is a repository copy of Macromolecular design of folic acid functionalized amylopectin-albumin core-shell nanogels for improved physiological stability and colon cancer cell targeted delivery of curcumin.

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