Regulation of Autophagy by Kinases

Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

doi:10.3390/cancers3022630

Cited by 163 publications

(142 citation statements)

References 196 publications

(222 reference statements)

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“…Mammucari et al reported that autophagy in mouse muscle was regulated by mTOR complex 2 (mTORC2, rapamycin-insensitive) rather than mTORC1 (rapamycin-sensitive), and injection of rapamycin did not induce autophagy in skeletal muscle in mice [31]. It is well established that mTORC1 directly suppresses autophagy, and mTORC2 may also regulate autophagy via Akt [32]. We did not observe a change in protein levels of p-Akt in human patient muscle cells after rapamycin treatment (data not shown) suggesting that the induction of autophagy in these cells was unlikely regulated by mTORC2-Akt signaling.…”

Section: Discussionmentioning

confidence: 99%

Correction of glycogen storage disease type III with rapamycin in a canine model

Brooks

Thurberg

et al. 2014

J Mol Med

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Recently, we reported that progression of liver fibrosis and skeletal myopathy caused by extensive accumulation of cytoplasmic glycogen at advanced age is the major feature of a canine model of glycogen storage disease (GSD) IIIa. Here, we aim to investigate whether rapamycin, a specific inhibitor of mTOR, is an effective therapy for GSD III. Our data show that rapamycin significantly reduced glycogen content in primary muscle cells from human patients with GSD IIIa by suppressing the expression of glycogen synthase and glucose transporter 1. To test the treatment efficacy in vivo, rapamycin was daily administered to GSD IIIa dogs starting from age 2 (early-treatment group) or 8 months (late-treatment group), and liver and skeletal muscle biopsies were performed at age 12 and 16 months. In both treatment groups, muscle glycogen accumulation was not affected at age 12 months but significantly inhibited at 16 months. Liver glycogen content was reduced in the early-treatment group but not in the latetreatment group at age 12 months. Both treatments effectively reduced liver fibrosis at age 16 months, consistent with markedly inhibited transition of hepatic stellate cells into myofibroblasts, the central event in the process of liver fibrosis. Our results suggest a potential useful therapy for GSD III.

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Section: Discussionmentioning

confidence: 99%

Correction of glycogen storage disease type III with rapamycin in a canine model

Brooks

Thurberg

et al. 2014

J Mol Med

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“…Based on examination of several endpoints related to the autophagy flux (31), we demonstrated that accumulation of AVs was due to inhibition of autophagic degradation rather than induction of autophagic flux. In addition, several protein kinases and core molecular proteins, required for induction of autophagy such as Akt, AMPK, mitogen-activated protein kinase (ERK, p38 and JNK) (34), Beclin 1 and Bcl-2 (35), were not obviously changed after imidazole treatment (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

Imidazole inhibits autophagy flux by blocking autophagic degradation and triggers apoptosis via increasing FoxO3a-Bim expression

Liu

Wang

Zhao

et al. 2014

International Journal of Oncology

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Abstract. Imidazole, an organic alkaloid, is an important pharmacophore in drug discovery. Anti-neoplastic potential of imidazole derivatives has been documented in several studies; however, mechanisms by which tumor cells respond to these stimuli remain to be elucidated. Autophagy and apoptosis have key roles in tumorigenesis and tumor treatment. In this study, we systematically examined autophagic events induced by imidazole in HEC-1B cells. Accumulation of autophagic vacuoles in imidazole-treated cells was verified by conversion of LC3 protein, as well as confocal and transmission electron microscopy. Furthermore, imidazole blocked autophagic degradation by impairing maturation of autophagosomes into autolysosomes. Concurrently, imidazole treatment induced apoptosis in HEC-1B cells, accompanied by activation of caspase 9 and 3. The proapoptotic effect was mediated by increased Bim expression. Moreover, imidazole upregulated the protein level of Foxo3a and induced its increased nuclear localisation. In addition, siRNA-mediated silencing of FoxO3a effectively attenuated imidazole-induced Bim upregulation and cell death, indicating direct involvement of this pathway in the imidazole-induced apoptosis. Taken together, our data provided a molecular link between imidazoles and anticancer therapies; understanding of these properties of imidazole is essential for development of effective cancer therapeutics using imidazoles.

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“…Although an increasing number of studies suggest that ERK is involved in modulating autophagy, the roles of ERK in autophagy are diverse (67). ERK signaling regulates the expression of autophagy and lysosomal genes by regulating the nuclear localization of transcription factor EB (TFEB) (63).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Autophagic Activation by Rta of Epstein-Barr Virus via the Extracellular Signal-Regulated Kinase Pathway

Hung

Chen

Wang

et al. 2014

J Virol

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Autophagy is an intracellular degradation pathway that provides a host defense mechanism against intracellular pathogens. However, many viruses exploit this mechanism to promote their replication. This study shows that lytic induction of EpsteinBarr virus (EBV) increases the membrane-bound form of LC3 (LC3-II) and LC3-containing punctate structures in EBV-positive cells. Transfecting 293T cells with a plasmid that expresses Rta also induces autophagy, revealing that Rta is responsible for autophagic activation. The activation involves Atg5, a key component of autophagy, but not the mTOR pathway. The expression of Rta also activates the transcription of the genes that participate in the formation of autophagosomes, including LC3A, LC3B, and ATG9B genes, as well as those that are involved in the regulation of autophagy, including the genes TNF, IRGM, and TRAIL. Additionally, treatment with U0126 inhibits the Rta-induced autophagy and the expression of autophagy genes, indicating that the autophagic activation is caused by the activation of extracellular signal-regulated kinase (ERK) signaling by Rta. Finally, the inhibition of autophagic activity by an autophagy inhibitor, 3-methyladenine, or Atg5 small interfering RNA, reduces the expression of EBV lytic proteins and the production of viral particles, revealing that autophagy is critical to EBV lytic progression. This investigation reveals how an EBV-encoded transcription factor promotes autophagy to affect viral lytic development. IMPORTANCEAutophagy is a cellular process that degrades and recycles nutrients under stress conditions to promote cell survival. Although autophagy commonly serves as a defense mechanism against viral infection, many viruses exploit this mechanism to promote their replication. This study finds that a transcription factor that is encoded by Epstein-Barr virus (EBV), Rta, activates autophagy, and the inhibition of autophagy reduces the ability of the virus to express viral lytic proteins and to generate progeny. Unlike other virus-encoded proteins that modulate autophagy by interacting with proteins that are involved in the autophagic pathway, Rta activates the transcription of the autophagy-related genes via the ERK pathway. The results of this study reveal how the virus manipulates autophagy to promote its lytic development.

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Regulation of Autophagy by Kinases

Cited by 163 publications

References 196 publications

Correction of glycogen storage disease type III with rapamycin in a canine model

Correction of glycogen storage disease type III with rapamycin in a canine model

Imidazole inhibits autophagy flux by blocking autophagic degradation and triggers apoptosis via increasing FoxO3a-Bim expression

Regulation of Autophagic Activation by Rta of Epstein-Barr Virus via the Extracellular Signal-Regulated Kinase Pathway

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