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1.
Cell Death Differ ; 27(8): 2344-2362, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32051546

RESUMO

Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.


Assuntos
Diferenciação Celular , Proteínas Substratos do Receptor de Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Músculo Esquelético/fisiologia , Mioblastos/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regeneração/fisiologia , Proteínas rab5 de Ligação ao GTP/metabolismo , Animais , Linhagem Celular , Células HEK293 , Membro Posterior/metabolismo , Humanos , Membranas Intracelulares/metabolismo , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular/genética , Mioblastos/metabolismo , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/genética , Proteínas rab5 de Ligação ao GTP/genética
2.
ChemSusChem ; 13(2): 298-303, 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31713317

RESUMO

The introduction of phosphorus functional groups into the skeleton of thioflavones is an attractive task and of great significance. Herein, a metal-free visible-light-induced radical cascade cyclization was developed for the preparation of 2-phosphorylated thioflavones from methylthiolated alkynones and phosphine oxides. In water as a green reaction medium, a large number of such 2-phosphorylated thioflavones were prepared, catalyzed by 4CzIPN [1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene] under visible-light irradiation. These reactions could be performed at ambient temperature and feature simple operation, wide reaction scope, and recyclability of aqueous media.

3.
Aging Cell ; 18(5): e13003, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313490

RESUMO

Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration, while the underlying mechanism remains elusive. Recent studies disclosed the emerging roles of heat-shock proteins in regulating muscle regeneration and homeostasis. Here, we found that Hsp90ß, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90ß-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90ß in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90ß preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90ß interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90ß in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90ß in regulating p53 stability to suppress senescence both in vitro and in vivo.


Assuntos
Senescência Celular , Proteínas de Choque Térmico HSP90/metabolismo , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Proteínas de Choque Térmico HSP90/química , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/química
4.
Org Lett ; 21(11): 4019-4024, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31099576

RESUMO

A novel and practical fluoroalkyl radical-initiated cascade reaction was developed to access diverse 2-fluoroalkylbenzothiazoles by reacting various fluoroalkyl radical sources, including perfluoroalkyl iodide (IC nF2 n+1, n = 3-8, 10), ICF(CF3)2, ICF2COOEt, ICF2CF2Cl, or ICF2CF2Br, tetramethylethane-1,2-diamine (TMEDA), and 2-isocyanoaryl thioethers in tetrahydrofuran under nitrogen atmosphere and blue-light irradiation conditions. Furthermore, this one-pot protocol could well be expanded to access various 2-fluoroalkylbenzoselenazoles starting from (2-isocyanophenyl)(methyl)selane, perfluoroalkyl iodides (IC nF2 n+1, n = 3-8) or ICF2COOEt and TMEDA.

5.
J Org Chem ; 83(23): 14419-14430, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30383381

RESUMO

An efficient copper-catalyzed radical cascade cyclization strategy was developed, by which a wide variety of 3-sulfonyl substituted indenones were prepared in one pot via reaction of 2-alkynylbenzonitriles with sulfonyl hydrazides in the presence of TBHP and CuI under mild reaction conditions. Much more importantly, the 3-sulfonyl indenones, synthesized through our newly developed copper-catalyzed radical cascade cyclization strategy, were found to own typical aggregation-induced emission (AIE) properties, showing orange to red emission with large Stokes shift (more than 135 nm). In addition, such newly found AIEgens could be successfully used in live cell imaging, exhibiting excellent biocompatibility and application potential.

6.
Mol Cell Biol ; 38(24)2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30275345

RESUMO

The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Regeneração/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Regulação para Baixo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/fisiologia , Mioblastos/fisiologia , Regulação para Cima/fisiologia
7.
Stem Cells ; 36(4): 527-539, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29315990

RESUMO

Tendon repair is a clinical challenge because of the limited understanding on tenogenesis. The synthesis of type I collagen (Collagen I) and other extracellular matrix are essential for tendon differentiation and homeostasis. Current studies on tenogenesis focused mostly on the tenogenic transcriptional factors while the signaling controlling tenogenesis on translational level remains largely unknown. Here, we showed that mechanistic target of rapamycin (mTOR) signaling was activated by protenogenic growth factor, transforming growth factors beta1, and insulin-like growth factor-I. The expression of mTOR was upregulated during tenogenesis of mesenchymal stem cells (MSCs). Moreover, mTOR was downregulated in human tendinopathy tissues and was inactivated upon statin treatment. Both inhibition and depletion of AKT or mTOR significantly reduced type I collagen production and impaired tenogenesis of MSCs. Tendon specific-ablation of mTOR resulted in tendon defect and reduction of Collagen I. However, there is no evident downregulation of tendon associated collagens at the transcription level. Our study demonstrated that AKT-mTOR axis is a key mediator of tendon differentiation and provided a novel therapeutic target for tendinopathy and tendon injuries. Stem Cells 2018;36:527-539.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Tendões/metabolismo , Animais , Células-Tronco Mesenquimais/citologia , Camundongos , Tendões/citologia , Fator de Crescimento Transformador beta1/metabolismo
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