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Seoul, South Korea

Seo K.-S.,Chungnam National University | Park J.-H.,Chungnam National University | Heo J.-Y.,Chungnam National University | Jing K.,Chungnam National University | And 11 more authors.
Oncogene | Year: 2015

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production and promotes tumour growth. Sirtuins are NAD(+)-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells. Source


Seo K.-S.,Chungnam National University | Park J.-H.,Chungnam National University | Heo J.-Y.,Chungnam National University | Jing K.,Chungnam National University | And 11 more authors.
Oncogene | Year: 2014

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production and promotes tumour growth. Sirtuins are NAD+-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD+/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells.Oncogene advance online publication, 31 March 2014; doi:10.1038/onc.2014.76. Source


Lee W.-K.,Kookmin University | Baek J.-H.,Diatech Korea Co. | Ryoo S.W.,Korean Institute of Tuberculosis | Yu Y.G.,Kookmin University
Bulletin of the Korean Chemical Society | Year: 2014

A derivative of Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been used for the preparation of tuberculosis vaccines. To establish a Korean tuberculosis vaccine derived from BCG-Pasteur 1173P2, genome sequencing of a BCG-Korea strain was completed by Joung and coworkers. 1 A comparison analysis of the genome sequences of the BCG-Pasteur 1173P2 and BCG-Korea strains showed marginal increases in the total genome length (~0.05%) and the number of genes (~4%) in the BCG-Korea genome. However, how the genomic changes affect the BCG-Korea protein expression levels remains unknown. Here, we provide evidence of the proteomic alterations in the BCG-Korea strain by using a SWATH-based mass spectrometric approach (Sequential Window Acquisition of all THeoretical mass spectra). Twenty BCG proteins were selected by top-rank identification in the BCG proteome analysis and the proteins were quantified by the SWATH method. Thirteen of 20 proteins showing significant changes were enough to discriminate between the two BCG proteomes. The SWATH method is very straightforward and provides a promising approach owing to its strong reliability and reproducibility during the proteomic analysis. Source


Jeon A.,Sogang University | Lee J.H.,Sogang University | Kwon H.S.,Sogang University | Park H.S.,Diatech Korea Co. | And 2 more authors.
Mass Spectrometry Letters | Year: 2013

In the present study, we report that the charge-directed (assisted) peptide dissociation products, such as b- and y-type peptide backbone fragments, were the major products in MS/MS and MS3 applications of some o-TEMPO-Bz-C(O)-peptide ions, while radical-driven dissociation products, such as a/x and c/z-type fragments, were previously shown to be the major products in the free radical initiated peptide sequencing mass spectrometry (FRIPS MS). Those o-TEMPO-Bz-C(O)-peptides share a common feature in their sequences, that is, the peptides do not include an arginine residue that has the highest proton affinity among free amino acids. The appearance of b- and y-type fragments as major products in FRIPS MS can be understood in terms of the so-called "mobile-proton model". When the proton is highly mobilized by the absence of arginine, the chare-directed peptide dissociation pathways appear to be more competitive than the radical-driven dissociation pathways, in our FRIPS experiments. Source


Kang G.-Y.,Diatech Korea Co. | Bang J.Y.,Diatech Korea Co. | Choi A.J.,Konkuk University | Yoon J.,Konkuk University | And 8 more authors.
Journal of Proteome Research | Year: 2014

Age-related macular degeneration (AMD) describes the progressive degeneration of the retinal pigment epithelium (RPE), retina, and choriocapillaris and is the leading cause of blindness in people over 50. The molecular mechanisms underlying this multifactorial disease remain largely unknown. To uncover novel secretory biomarkers related to the pathogenesis of AMD, we adopted an integrated approach to compare the proteins identified in the conditioned medium (CM) of cultured RPE cells and the exosomes derived from CM and from the aqueous humor (AH) of AMD patients by LC-ESI-MS/MS. Finally, LC-MRM was performed on the AH from patients and controls, which revealed that cathepsin D, cytokeratin 8, and four other proteins increased in the AH of AMD patients. The present study has identified potential biomarkers and therapeutic targets for AMD treatment, such as proteins related to the autophagy-lysosomal pathway and epithelial-mesenchymal transition, and demonstrated a novel and effective approach to identifying AMD-associated proteins that might be secreted by RPE in vivo in the form of exosomes. The proteomics-based characterization of this multifactorial disease could help to match a particular marker to particular target-based therapy in AMD patients with various phenotypes. © 2014 American Chemical Society. Source

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