Depletion of p18/LAMTOR1 promotes cell survival via activation of p27<sup>kip1</sup>‐dependent autophagy under starvation

Zada, Sahib; Noh, Hae Sook; Baek, Seung-Myeong; Ha, Ji Won; Hahm, Jong Ryeal; Kim, Deok Ryong

doi:10.1002/cbin.10497

Cited by 13 publications

(5 citation statements)

References 34 publications

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“…Conditional deletion of Rictor in the postnatal murine forebrain greatly reduced mTORC2 activity and dendritic spine density in CA1 pyramidal neurons ( Huang et al, 2013 ). Finally, p18 has been shown to directly interact with p27 (kip1), thereby regulating RhoA activity and actin remodeling ( Hoshino et al, 2011 ), and autophagic activity ( Zada et al, 2015 ). Whether these mTOR-independent p18 functions play any role in synaptic plasticity and brain development remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

Sun

Liu

Jia

et al. 2018

eLife

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Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory.

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Section: Discussionmentioning

confidence: 99%

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

Sun

Liu

Jia

et al. 2018

eLife

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“…Another example of enhanced macroautophagy by CKIs is provided by p27, which restricts the cell cycle at G1 phase through binding to and inhibiting CDK2-cyclin E and CDK4-cyclin D complex. Beyond braking cell cycle, p27 controls the balance between macroautophagy and cell death upon different stressful stimulations 23,56-58. Both low energy status and amino acid starvation stabilize p27 through the energy-sensing LKB1-AMPK pathway-mediated phosphorylation at Thr198, leading to the induction of macroautophagy that senses nutrient concentration and promotes bioenergetics rather than cell death 23.…”

Section: Autophagy Regulation By Cell Cycle Regulatorsmentioning

confidence: 99%

Selective Autophagy Regulates Cell Cycle in Cancer Therapy

et al. 2019

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Aberrant function of cell cycle regulators results in uncontrolled cell proliferation, making them attractive therapeutic targets in cancer treatment. Indeed, survival of many cancers exclusively relies on these proteins, and several specific inhibitors are in clinical use. Although the ubiquitin-proteasome system is responsible for the periodic quality control of cell cycle proteins during cell cycle progression, increasing evidence clearly demonstrates the intimate interaction between cell cycle regulation and selective autophagy, important homeostasis maintenance machinery. However, these studies have often led to divergent rather than unifying explanations due to complexity of the autophagy signaling network, the inconsistent functions between general autophagy and selective autophagy, and the different characteristics of autophagic substrates. In this review, we highlight current data illustrating the contradictory and important role of cell cycle proteins in regulating autophagy. We also focus on how selective autophagy acts as a central mechanism to maintain orderly DNA repair and genome integrity by degrading specific cell cycle proteins, regulating cell division, and promoting DNA damage repair. We further discuss the ways in which selective autophagy may impact the cell cycle regulators, since failure to appropriately remove these can interfere with cell death-related processes, including senescence and autophagy-related cell death. Imbalanced cell proliferation is typically utilized by cancer cells to acquire resistance. Finally, we discuss the possibility of a potent anticancer therapeutic strategy that targets selective autophagy or autophagy and cell cycle together.

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“…This finding is confirmed by experiments in p27 −/− MEFs that, when deprived of amino acids, show autophagy resistance. In this specific genetic setting and condition, autophagy activation was further inhibited through the sequestration in the cytosol of the transcription factor TFEB, which controls the expression of genes involved in lysosomal biogenesis and autophagy [ 83 ].…”

Section: P27 and P57 Proteins’ Major Features Properties And Funmentioning

confidence: 99%

Regulation of p27Kip1 and p57Kip2 Functions by Natural Polyphenols

et al. 2020

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In numerous instances, the fate of a single cell not only represents its peculiar outcome but also contributes to the overall status of an organism. In turn, the cell division cycle and its control strongly influence cell destiny, playing a critical role in targeting it towards a specific phenotype. Several factors participate in the control of growth, and among them, p27Kip1 and p57Kip2, two proteins modulating various transitions of the cell cycle, appear to play key functions. In this review, the major features of p27 and p57 will be described, focusing, in particular, on their recently identified roles not directly correlated with cell cycle modulation. Then, their possible roles as molecular effectors of polyphenols’ activities will be discussed. Polyphenols represent a large family of natural bioactive molecules that have been demonstrated to exhibit promising protective activities against several human diseases. Their use has also been proposed in association with classical therapies for improving their clinical effects and for diminishing their negative side activities. The importance of p27Kip1 and p57Kip2 in polyphenols’ cellular effects will be discussed with the aim of identifying novel therapeutic strategies for the treatment of important human diseases, such as cancers, characterized by an altered control of growth.

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Depletion of p18/LAMTOR1 promotes cell survival via activation of p27^kip1‐dependent autophagy under starvation

Cited by 13 publications

References 34 publications

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

Selective Autophagy Regulates Cell Cycle in Cancer Therapy

Regulation of p27Kip1 and p57Kip2 Functions by Natural Polyphenols

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Depletion of p18/LAMTOR1 promotes cell survival via activation of p27kip1‐dependent autophagy under starvation

Cited by 13 publications

References 34 publications

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

Selective Autophagy Regulates Cell Cycle in Cancer Therapy

Regulation of p27Kip1 and p57Kip2 Functions by Natural Polyphenols

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Product

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Depletion of p18/LAMTOR1 promotes cell survival via activation of p27^kip1‐dependent autophagy under starvation