02646nas a2200217 4500008004100000022001400041245010800055210006900163260010300232300001400335490000700349520178900356653001002145653003602155653002402191653002802215653001902243100001902262700001802281856012902299 2013 eng d a0300-908400aEffect of different arginine methylations on the thermodynamics of tat peptide binding to HIV-1 TAR RNA0 aEffect of different arginine methylations on the thermodynamics  a23 RUE LINOIS, 75724 PARIS, FRANCEbELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIERcJUL a1422-14310 v953 a

RNA-binding proteins are an important class of mediators that regulate cell function and differentiation. Methylation of arginine, a post-translational modification (PTM) found in these proteins, can modulate their function. Arginine can be monomethylated or dimethylated, depending on the type of methyl transferases involved. This paper describes a comparative study of the thermodynamics of unmodified and modified Tat peptide interaction with TAR RNA, where the peptide is methylated at epsilon (epsilon) and eta (eta) nitrogen atoms of guanidinium group of arginine side chain at position 52 or 53. The results indicate that monomethylation of arginine at epsilon (epsilon) nitrogen atom enhances binding affinity, owing to a more favourable enthalpy component which overrides the less favourable entropy change. In contrast, monomethylation of arginine residue at eta nitrogen results in reduced binding affinity originating exclusively from a less favourable enthalpy change leaving entropic component unaffected. However, in case of simultaneous methylation at epsilon and eta positions, the binding parameters remain almost unaffected, when compared to the unmodified peptide. In case of symmetric dimethylation at eta position the observed enthalpy change of the binding was found to be smaller than the values obtained for the unmodified peptide. Asymmetric dimethylation at eta position showed the most reduced binding affinities owing to less favourable enthalpy changes. These results provide insights that enable elucidation of the biological outcome of arginine methylation as PTMs that regulate protein function, and will contribute to our understanding of how these PTMs are established in vitro and in vivo. (C) 2013 Elsevier Masson SAS. All rights reserved.

10aHIV-110aPost-translational modification10aProtein methylation10aRNA-protein interaction10aThermodynamics1 aKumar, Santosh1 aMaiti, Souvik uhttps://library.ncl.res.in/content/effect-different-arginine-methylations-thermodynamics-tat-peptide-binding-hiv-1-tar-rna-002428nas a2200157 4500008004100000022001400041245011700055210006900172260009100241300001600332490000600348520175000354100001902104700001802123856012902141 2013 eng d a1932-620300aEffect of N-acetylation and N-methylation of lysine residue of tat peptide on its interaction with HIV-1 TAR RNA0 aEffect of Nacetylation and Nmethylation of lysine residue of tat a1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USAbPUBLIC LIBRARY SCIENCEcOCT aUNSP e775950 v83 a

Post-translational modification (PTM) of RNA binding proteins (RBPs) play a very important role in determining their binding to cognate RNAs and therefore regulate the downstream effects. Lysine can undergo various PTMs and thereby contribute to the regulation of different cellular processes. It can be reversibly acetylated and methylated using a pool of respective enzymes, to act as a switch for controlling the binding efficiency of RBPs. Here we have delineated the thermodynamic and kinetic effects of N-acetylation and N-monomethylation of lysine on interaction between HIV-1 TAR RNA and its cognate binder Tat peptide (a model system). Our results indicate that acetylation of lysine 50 (K50), leads to eight-fold reduction in binding affinity, originating exclusively from entropy changes whereas, lysine 51 (K51) acetylation resulted only in three fold decrease with large enthalpy-entropy compensation. The measurement of kinetic parameters indicated major change (4.5 fold) in dissociation rate in case of K50 acetylation however, K51 acetylation showed similar effect on both association and dissociation rates. In contrast, lysine methylation did not affect the binding affinity of Tat peptide to TAR RNA at K50, nonetheless three fold enhancement in binding affinity was observed at K51 position. In spite of large enthalpy-entropy compensation, lysine methylation seems to have more pronounced position specific effect on the kinetic parameters. In case of K50 methylation, simultaneous increase was observed in the rate of association and dissociation leaving binding affinity unaffected. The increased binding affinity for methylated Tat at K51 stems from faster association rate with slightly slower dissociation rate.

1 aKumar, Santosh1 aMaiti, Souvik uhttps://library.ncl.res.in/content/effect-n-acetylation-and-n-methylation-lysine-residue-tat-peptide-its-interaction-hiv-1-002898nas a2200313 4500008004100000022001400041245015200055210006900207260000800276300000700284490000700291520187700298653001702175653001402192653001802206653001402224653001502238653000902253100001802262700001902280700002002299700001902319700002202338700002002360700001702380700003702397700002102434856012902455 2018 eng d a1471-240700aEpoxyazadiradione suppresses breast tumor growth through mitochondrial depolarization and caspase-dependent apoptosis by targeting PI3K/Akt pathway0 aEpoxyazadiradione suppresses breast tumor growth through mitocho cJAN a520 v183 a

Background: Breast cancer is one of the most commonly diagnosed invasive cancers among women around the world. Among several subtypes, triple negative breast cancer (TNBC) is highly aggressive and chemoresistant. Treatment of TNBC patients has been challenging due to heterogeneity and devoid of well-defined molecular targets. Thus, identification of novel effective and selective agents against TNBC is essential. Methods: We used epoxyazadiradione to assess the cell viability, mitochondrial potential, ROS level, cell migration, apoptosis and protein expression in cell culture models of TNBC MDA-MB-231 and ER+MCF-7 breast cancer cells. The molecular mechanism was examined in two different type of breast cancer cells in response to epoxyazadiradione. We have also analyzed the effect of epoxyazadiradione on breast tumor growth using in vivo mice model. Results: In this study, we for the first time investigated that out of 10 major limonoids isolated from Azadirachta indica, epoxyazadiradione exhibits most potent anti-cancer activity in both TNBC and ER+breast cancer cells. Epoxyazadiradione induces apoptosis and inhibits PI3K/Akt-mediated mitochondrial potential, cell viability, migration and angiogenesis. It also inhibits the expression of pro-angiogenic and pro-metastatic genes such as Cox2, OPN, VEGF and MMP-9 in these cells. Furthermore, epoxyazadiradione attenuates PI3K/Akt- mediated AP-1 activation. Our in vivo data revealed that epoxyazadiradione suppresses breast tumor growth and angiogenesis in orthotopic NOD/SCID mice model. Conclusion: Our findings demonstrate that epoxyazadiradione inhibits PI3K/Akt-dependent mitochondrial depolarisation, induces apoptosis and attenuates cell migration, angiogenesis and breast tumor growth suggesting that this compound may act as a potent therapeutic agent for the management of breast cancer.

10aAngiogenesis10aApoptosis10aBreast cancer10aLimonoids10aMetastasis10aPI3K1 aKumar, Dhiraj1 aHaldar, Saikat1 aGorain, Mahadeo1 aKumar, Santosh1 aMulani, Fayaj, A.1 aYadav, Amit, S.1 aMiele, Lucio1 aThulasiram, Hirekodathakallu, V.1 aKundu, Gopal, C. uhttps://library.ncl.res.in/content/epoxyazadiradione-suppresses-breast-tumor-growth-through-mitochondrial-depolarization-and