The AMPK/p27Kip1 Pathway as a Novel Target to Promote Autophagy and Resilience in Aged Cells

McKay, Lauren K; White, James P.

doi:10.3390/cells10061430

Cited by 22 publications

(16 citation statements)

References 103 publications

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“…In the nucleus, p27 Kip1 inhibits the cell cycle progression and makes the cell susceptible to quiescence and apoptosis. However, in the cytoplasm, p27 Kip1 has been found to promote cellular resilience through autophagy and anti-apoptotic mechanisms [98]. Altogether, all these nuclear and extra-nuclear functions allow a correct neurogenesis, maintaining a quiescent state in the post-mitotic neurons.…”

Section: Discussionmentioning

confidence: 99%

“…The cyclin-dependent kinase inhibitor p27 Kip1 (named p27) participates in many biological processes, such as cell proliferation, differentiation, migration and apoptosis [97]. p27 has been extensively studied for its role in cancer as a tumor suppressor [98]. It plays fundamental roles in all phases of the cell division cycle.…”

Section: P27 Kip1 and Its Role In The Cell Cycle Progressionmentioning

confidence: 99%

“…It has been suggested that p27 can drive apoptosis or autophagy following AMPK activation. AMPK phosphorylation of p27 on Thr198 promotes p27 protein stability and increases the levels of cytoplasmatic p27, resulting in greater autophagy and fewer apoptotic processes [98]. Other authors have proposed that the mechanism responsible for p27-controlled autophagy is regulated via mTOR (mammalian target of rapamycin) [117].…”

Section: P27 and Admentioning

confidence: 99%

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p27, The Cell Cycle and Alzheimer´s Disease

García‐Osta

Dong

Moreno-Aliaga

et al. 2022

IJMS

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The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27Kip1. At the nuclear level, p27Kip1 has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27Kip1, including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer’s disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27Kip1 levels and phosphorylation status have been described in AD. Increased levels of Ab42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27Kip1 post-transcriptional modifications, causing a disbalance between the levels and functions of p27Kip1 in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27Kip1 in AD and the therapeutic opportunities associated with the modulation of this target.

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Section: Discussionmentioning

confidence: 99%

Section: P27 Kip1 and Its Role In The Cell Cycle Progressionmentioning

confidence: 99%

Section: P27 and Admentioning

confidence: 99%

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p27, The Cell Cycle and Alzheimer´s Disease

García‐Osta

Dong

Moreno-Aliaga

et al. 2022

IJMS

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“…It has been proposed that nuclear p27 promotes quiescence, apoptosis, and senescence, while cytoplasmic p27 enhances cell survival and autophagy. Aging has been related with a greater expression of nuclear p27 in several cell types [ 46 ]. Therefore, it would be of interest for future studies to characterize at protein level the changes in cellular location of p27 in adipose tissue during aging.…”

Section: Discussionmentioning

confidence: 99%

Regulation of p27 and Cdk2 Expression in Different Adipose Tissue Depots in Aging and Obesity

Colón-Mesa

Fernández‐Galilea

Sáinz

et al. 2021

IJMS

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Aging usually comes associated with increased visceral fat accumulation, reaching even an obesity state, and favoring its associated comorbidities. One of the processes involved in aging is cellular senescence, which is highly dependent on the activity of the regulators of the cell cycle. The aim of this study was to analyze the changes in the expression of p27 and cdk2 in different adipose tissue depots during aging, as well as their regulation by obesity in mice. Changes in the expression of p27 and CDK2 in visceral and subcutaneous white adipose tissue (WAT) biopsies were also analyzed in a human cohort of obesity and type 2 diabetes. p27, but not cdk2, exhibits a lower expression in subcutaneous than in visceral WAT in mice and humans. p27 is drastically downregulated by aging in subcutaneous WAT (scWAT), but not in gonadal WAT, of female mice. Obesity upregulates p27 and cdk2 expression in scWAT, but not in other fat depots of aged mice. In humans, a significant upregulation of p27 was observed in visceral WAT of subjects with obesity. Taken together, these results show a differential adipose depot-dependent regulation of p27 and cdk2 in aging and obesity, suggesting that p27 and cdk2 could contribute to the adipose-tissue depot’s metabolic differences. Further studies are necessary to fully corroborate this hypothesis.

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“…On the one hand, the tumor suppressor role of p27 KIP1 is primarily associated with its nuclear form-enhancing cell-cycle inhibition and sensitivity to cellular senescence and apoptosis [ 28 ]. On the other hand, cytoplasmic p27 KIP1 drives survival mechanisms, notably through the activation of autophagy [ 29 ]. Indeed, constitutive expression and accumulation of p27 KIP1 induce autophagy in glioma cells and myeloma [ 28 , 30 ].…”

Section: Cell-cycle Regulators Modulate Autophagymentioning

confidence: 99%

The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer

Ziegler

Huber

Fajas

2021

Cancers

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In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes the efficient recycling of endogenous components from both extrinsic stress, e.g., nutrient deprivation, and intrinsic sub-lethal damage. Mediating cellular homeostasis and cytoprotection, autophagy is found to be dysregulated in numerous pathophysiological contexts, such as cancer. As an adaptative advantage, the upregulation of autophagy allows tumor cells to integrate stress signals, escaping multiple cell death mechanisms. Nevertheless, the precise role of autophagy during tumor development and progression remains highly context-dependent. Recently, multiple articles has suggested the importance of various cell cycle regulators in the modulation of autophagic processes. Here, we review the current clues indicating that cell-cycle regulators, including cyclin-dependent kinase inhibitors (CKIs), cyclin-dependent kinases (CDKs), and E2F transcription factors, are intrinsically linked to the regulation of autophagy. As an increasing number of studies highlight the importance of autophagy in cancer progression, we finally evoke new perspectives in therapeutic avenues that may include both cell cycle inhibitors and autophagy modulators to synergize antitumor efficacy.

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The AMPK/p27Kip1 Pathway as a Novel Target to Promote Autophagy and Resilience in Aged Cells

Cited by 22 publications

References 103 publications

p27, The Cell Cycle and Alzheimer´s Disease

p27, The Cell Cycle and Alzheimer´s Disease

Regulation of p27 and Cdk2 Expression in Different Adipose Tissue Depots in Aging and Obesity

The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer

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