A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress

Holczer, Marianna; Hajdú, Bence; Lőrincz, Tamás; Szarka, András; Bánhegyi, Gábor; Kapuy, Orsolya

doi:10.3390/ijms20225543

Cited by 60 publications

(62 citation statements)

References 47 publications

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“…AMPK and mTORC1) and the key component of autophagy inducer, called ULK1. We claimed that AMPK-P-mTORC1 and mTORC1-ULK1-P double negative feedback loops are required for the switch-like characteristic of the system 23 . However, we have not analysed the importance of the negative feedback loops of mTORC1-AMPK-P-ULK1-P controlled network The markers of autophagy (LC3, p62) and ULK1-P (ULK1-555-P, ULK1-777-P) were followed by immunoblotting.…”

Section: Discussionmentioning

confidence: 99%

“…In this study we directly focus on AMPK-P → ULK1-P ┤ AMPK-P negative feedback loop to try to understand the dynamical features of this feedback loop in details by applying both molecular and theoretical biological techniques. Therefore, our previously published mathematical model was used for describing mTORC1-AMPK-P-ULK1-P controlled autophagy 23 , however first direct positive AMPK-P → ULK1-P and negative ULK1-P ┤ AMPK-P connections are assumed (see the wiring diagram on Fig. 1).…”

Section: Direct Negative Feedback Loop Between Ampk-p and Ulk1-p Resumentioning

confidence: 99%

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Fine-tuning of AMPK–ULK1–mTORC1 regulatory triangle is crucial for autophagy oscillation

Holczer

Hajdú

Lőrincz

et al. 2020

Sci Rep

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Autophagy is an intracellular digestive process, which has a crucial role in maintaining cellular homeostasis by self-eating the unnecessary and/or damaged components of the cell at various stress events. ULK1, one of the key elements of autophagy activator complex, together with the two sensors of nutrient and energy conditions, called mTORC1 and AMPK kinases, guarantee the precise function of cell response mechanism. We claim that the feedback loops of AMPK–mTORC1–ULK1 regulatory triangle determine an accurate dynamical characteristic of autophagic process upon cellular stress. By using both molecular and theoretical biological techniques, here we reveal that a delayed negative feedback loop between active AMPK and ULK1 is essential to manage a proper cellular answer after prolonged starvation or rapamycin addition. AMPK kinase quickly gets induced followed by AMPK-P-dependent ULK1 activation, whereas active ULK1 has a rapid negative effect on AMPK-P resulting in a delayed inhibition of ULK1. The AMPK-P → ULK1 ˧ AMPK-P negative feedback loop results in a periodic repeat of their activation and inactivation and an oscillatory activation of autophagy, as well. We demonstrate that the periodic induction of self-cannibalism is necessary for the proper dynamical behaviour of the control network when mTORC1 is inhibited with respect to various stress events. By computational simulations we also suggest various scenario to introduce “delay” on AMPK-P-dependent ULK1 activation (i.e. extra regulatory element in the wiring diagram or multi-phosphorylation of ULK1).

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Section: Discussionmentioning

confidence: 99%

Section: Direct Negative Feedback Loop Between Ampk-p and Ulk1-p Resumentioning

confidence: 99%

Fine-tuning of AMPK–ULK1–mTORC1 regulatory triangle is crucial for autophagy oscillation

Holczer

Hajdú

Lőrincz

et al. 2020

Sci Rep

Self Cite

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“…Besides, mTORC1 can be activated or inhibited by various signaling pathways directly or indirectly. For instance, 5′-AMP-activated protein kinase (AMPK) activated by energy shortage is a crucial inhibitor of mTORC1 [18]. What's more, transcription factor c-Myc and p53 also take part in metabolic reprogramming through transcriptional regulation of metabolism-related genes [19,20].…”

Section: Cancer Metabolismmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

221

178

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Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

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“…BioMed Research International polymerase III, and decreased transcriptional readout [63,64]. Moreover, mTORC1 is involved in the negative feedback regulation of autophagy on upstream growth factor signaling during microtubule regulation [64][65][66].…”

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confidence: 99%

Associated Targets of the Antioxidant Cardioprotection of Ganoderma lucidum in Diabetic Cardiomyopathy by Using Open Targets Platform: A Systematic Review

Shaher

Qiu

Wang

et al. 2020

BioMed Research International

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Even with substantial advances in cardiovascular therapy, the morbidity and mortality rates of diabetic cardiomyopathy (DCM) continually increase. Hence, a feasible therapeutic approach is urgently needed. Objectives. This work is aimed at systemically reviewing literature and addressing cell targets in DCM through the possible cardioprotection of G. lucidum through its antioxidant effects by using the Open Targets Platform (OTP) website. Methods. The OTP website version of 19.11 was accessed in December 2019 to identify the studies in DCM involving G. lucidum. Results. Among the 157 cell targets associated with DCM, the mammalian target of rapamycin (mTOR) was shared by all evidence, drug, and text mining data with 0.08 score association. mTOR also had the highest score association 0.1 with autophagy in DCM. Among the 1731 studies of indexed PubMed articles on G. lucidum published between 1985 and 2019, 33 addressed the antioxidant effects of G. lucidum and its molecular signal pathways involving oxidative stress and therefore were included in the current work. Conclusion. mTOR is one of the targets by DCM and can be inhibited by the antioxidative properties of G. lucidum directly via scavenging radicals and indirectly via modulating mTOR signal pathways such as Wnt signaling pathway, Erk1/2 signaling, and NF-κB pathways.

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A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress

Cited by 60 publications

References 47 publications

Fine-tuning of AMPK–ULK1–mTORC1 regulatory triangle is crucial for autophagy oscillation

Fine-tuning of AMPK–ULK1–mTORC1 regulatory triangle is crucial for autophagy oscillation

The role of ubiquitination and deubiquitination in cancer metabolism

Associated Targets of the Antioxidant Cardioprotection of Ganoderma lucidum in Diabetic Cardiomyopathy by Using Open Targets Platform: A Systematic Review

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