Transduced Tat–SAG fusion protein protects against oxidative stress and brain ischemic insult

Kim, Dae Won; Lee, Sun Hwa; Jeong, Min Seop; Sohn, Eun Jeong; Kim, Mi Jin; Jeong, Hyung Jae; An, Jung Nam; Jang, Sang Ho; Won, Moo Ho; Hwang, In Koo; Cho, Sung‐Woo; Kang, Tae‐Cheon; Lee, Kil Soo; Park, Jinseu; Yoo, Ki‐Yeon; Eum, Won Sik; Choi, Soo Young

doi:10.1016/j.freeradbiomed.2010.01.023

Cited by 60 publications

(61 citation statements)

References 47 publications

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“…Tat-SOD and SOD were purified as described previously (10,11). Cells seeded in 6-well plates were grown to confluence and treated with or without silk peptide (0.2 μg/ml) for 1 h to assess the effect of silk peptide on the concentration-dependent transduction of Tat-SOD and SOD into HaCaT cells.…”

Section: Transduction Of Sod and Tat-sod Into Hacat Human Keratinocytesmentioning

confidence: 99%

Effect of silk fibroin peptide derived from silkworm Bombyx mori on the anti-inflammatory effect of Tat-SOD in a mice edema model

Kim¹,

Hwang²,

Kim³

et al. 2011

BMB Reports

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Section: Transduction Of Sod and Tat-sod Into Hacat Human Keratinocytesmentioning

confidence: 99%

Effect of silk fibroin peptide derived from silkworm Bombyx mori on the anti-inflammatory effect of Tat-SOD in a mice edema model

Kim¹,

Hwang²,

Kim³

et al. 2011

BMB Reports

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“…[23][24][25][26][27][28][29] In a previous study, the TAT protein was used to deliver SOD for the purpose of overcoming certain diseases, such as inflammation or osteoarthritis, and protecting against ischemic brain injury. [30][31][32][33] We developed an arginine-rich peptide, termed low molecular weight protamine (LMWP), which is derived from natural protamine. We demonstrated that LMWP achieved protein transduction in various cell types with activity equivalent to that of unconjugated TAT for molecular imaging and therapeutic purposes.…”

Section: Introductionmentioning

confidence: 99%

Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Lee¹,

Chung²,

Park³

2012

IJN

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Background Human dental pulp stem cells (DPSCs) have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1) was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP), and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation. Results LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21 Cip1 , induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide. Conclusion Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.

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“…When forming a complex with other components of SCF/CRL E3 ubiquitin ligases, SAG has E3 ubiquitin ligase activity (15,16,21) and promotes the ubiquitylation and subsequent degradation of various cellular proteins, including p27 (22,23), c-Jun (24), pro-caspase-3 (25), IκBα (16,26), HIF-1α (27), NOXA (28), and NF1 (18) in a cell context-dependent manner. Whole animal studies revealed that SAG overexpression protects mouse brain tissues from ischemia/hypoxia-induced damage (29,30). SAG transgenic expression in mouse skin inhibited tumor formation at the early stage by targeting c-Jun/AP1, but enhanced tumor growth at later stages in a DMBA-TPA carcinogenesis model by targeting IκBα to activate NF-κB (26) and promoted UVB-induced skin hyperplasia by targeting p27 (23).…”

mentioning

confidence: 99%

Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis

Tan

Jia

et al. 2014

J. Clin. Invest.

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Cullin-RING ligases (CRLs) are a family of E3 ubiquitin ligase complexes that rely on either RING-box 1 (RBX1) or sensitive to apoptosis gene (SAG), also known as RBX2, for activity. RBX1 and SAG are both overexpressed in human lung cancer; however, their contribution to patient survival and lung tumorigenesis is unknown. Here, we report that overexpression of SAG, but not RBX1, correlates with poor patient prognosis and more advanced disease. We found that SAG is overexpressed in murine Kras G12D -driven lung tumors and that Sag deletion suppressed lung tumorigenesis and extended murine life span. Using cultured lung cancer cells, we showed that SAG knockdown suppressed growth and survival, inactivated both NF-κB and mTOR pathways, and resulted in accumulation of tumor suppressor substrates, including p21, p27, NOXA, and BIM. Importantly, growth suppression by SAG knockdown was partially rescued by simultaneous knockdown of p21 or the mTOR inhibitor DEPTOR. Treatment with MLN4924, a small molecule inhibitor of CRL E3s, also inhibited the formation of Kras G12D -induced lung tumors through a similar mechanism involving inactivation of NF-κB and mTOR and accumulation of tumor suppressor substrates. Together, our results demonstrate that Sag is a Kras-cooperating oncogene that promotes lung tumorigenesis and suggest that targeting SAG-CRL E3 ligases may be an effective therapeutic approach for Kras-driven lung cancers.

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Transduced Tat–SAG fusion protein protects against oxidative stress and brain ischemic insult

Cited by 60 publications

References 47 publications

Effect of silk fibroin peptide derived from silkworm Bombyx mori on the anti-inflammatory effect of Tat-SOD in a mice edema model

Effect of silk fibroin peptide derived from silkworm Bombyx mori on the anti-inflammatory effect of Tat-SOD in a mice edema model

Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis

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