p27 controls Ragulator and mTOR activity in amino acid-deprived cells to regulate the autophagy–lysosomal pathway and coordinate cell cycle and cell growth

Nowosad, Ada; Jeannot, Pauline; Callot, Caroline; Creff, Justine; Perchey, Renaud T; Joffre, Carine; Codogno, Patrice; Manenti, Stéphane; Besson, Arnaud

doi:10.1038/s41556-020-0554-4

Cited by 89 publications

(84 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S 3A, B ). In these conditions, p27 −/− cells did not maintain elevated mTOR activity as observed under amino acid starvation 21 . In fact, p27 +/+ cells display increased p70 S6K1 phosphorylation upon glucose withdrawal compared to p27 −/− cells, which is associated with autophagy-related mTOR re-activation 49 , as indicated by the inhibition of mTORC1 activity following CQ treatment in p27 +/+ cells (Fig.…”

Section: Resultsmentioning

confidence: 74%

“…We recently found that in response to amino acid deprivation, p27 promotes autophagy by interfering with the assembly of the Ragulator complex, thereby participating in mTOR inhibition 21 . The lysosome-associated multiprotein complex BORC mediates MT-dependent trafficking of autophagosomes and lysosomes during autophagy and autophagosome–lysosome fusion 45 , 46 .…”

Section: Resultsmentioning

confidence: 99%

“…Increasing evidence indicates that cytoplasmic localization of p27 confers resistance to anticancer therapies and negatively affects cancer patient prognosis 7 , 8 . p27 may sustain cancer progression via several mechanisms, including the regulation of cell migration and invasion 9 – 12 , stemness 13 , 14 , and autophagy 15 – 21 .…”

Section: Introductionmentioning

confidence: 99%

“…p27 was recently implicated in the promotion of basal and stress-induced autophagy 15 – 21 . Following glucose and/or serum deprivation, LKB1 activates AMPK, which in turn phosphorylates p27 on T198, T170 and/or S83, causing its cytoplasmic retention and promoting autophagy 17 , 37 .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

et al. 2021

Self Cite

View full text Add to dashboard Cite

The cyclin-dependent kinase inhibitor p27Kip1 (p27) has been involved in promoting autophagy and survival in conditions of metabolic stress. While the signaling cascade upstream of p27 leading to its cytoplasmic localization and autophagy induction has been extensively studied, how p27 stimulates the autophagic process remains unclear. Here, we investigated the mechanism by which p27 promotes autophagy upon glucose deprivation. Mouse embryo fibroblasts (MEFs) lacking p27 exhibit a decreased autophagy flux compared to wild-type cells and this is correlated with an abnormal distribution of autophagosomes. Indeed, while autophagosomes are mainly located in the perinuclear area in wild-type cells, they are distributed throughout the cytoplasm in p27-null MEFs. Autophagosome trafficking towards the perinuclear area, where most lysosomes reside, is critical for autophagosome–lysosome fusion and cargo degradation. Vesicle trafficking is mediated by motor proteins, themselves recruited preferentially to acetylated microtubules, and autophagy flux is directly correlated to microtubule acetylation levels. p27−/− MEFs exhibit a marked reduction in microtubule acetylation levels and restoring microtubule acetylation in these cells, either by re-expressing p27 or with deacetylase inhibitors, restores perinuclear positioning of autophagosomes and autophagy flux. Finally, we find that p27 promotes microtubule acetylation by binding to and stabilizing α-tubulin acetyltransferase (ATAT1) in glucose-deprived cells. ATAT1 knockdown results in random distribution of autophagosomes in p27+/+ MEFs and impaired autophagy flux, similar to that observed in p27−/− cells. Overall, in response to glucose starvation, p27 promotes autophagy by facilitating autophagosome trafficking along microtubule tracks by maintaining elevated microtubule acetylation via an ATAT1-dependent mechanism.

show abstract

Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this research, we found that p27 Kip1, CDK2, and cyclin D1 were the downstream targets of SNORA47 by which SNORA47 shRNA regulated cell cycle distribution of NSCLC. P27 Kip1 is known to be a cell cycle regulator which plays a pivotal role in the G1-to-S transition of the cell cycle ( 18 – 20 ). Consistently, our data demonstrated that SNORA47 knockdown could result in G1 phase arrest in NSCLC cells through upregulation of p27 Kip1.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of SNORA47 Inhibits the Tumorigenesis of NSCLC via Mediation of PI3K/Akt Signaling Pathway

Tian

Ling

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

BackgroundNon-small cell lung cancer (NSCLC) is a frequently diagnosed aggressive cancer all over the world. Small nucleolar RNAs (snoRNAs) are a group of non-coding mediatory RNAs. A previous report indicated that small nucleolar RNA 47 (SNORA47) is upregulated in NSCLC. However, the role of SNORA47 in NSCLC is unclear.Material and MethodsCell proliferation was measured by immunofluorescence staining. Cell apoptosis and cycle of NSCLC were tested by flow cytometry and the protein expressions were investigated by Western-blot. Meanwhile, cell migration and invasion were detected by transwell assay. Xenograft mice model was established to detect the effect of SNORA47 knockdown on tumor growth of NSLC in vivo.ResultsKnockdown of SNORA47 significantly inhibited the proliferation of NSCLC cells via inducing cell apoptosis. Moreover, migration and invasion of NSCLC cells were notably decreased by SNORA47 shRNA. SNORA47 knockdown significantly induced G1 arrest in NSCLC cells via regulation of p27 Kip1, CDK2, and cyclin D1. Meanwhile, SNORA47 shRNA inhibited EMT process and PI3K/Akt signaling in NSCLC cells. Finally, silencing of SNORA47 significantly inhibited the tumor growth of NSCLC in vivo.ConclusionKnockdown of SNORA47 significantly inhibited the tumorigenesis of NSCLC via inhibition of PI3K/Akt signaling and EMT process. Thereby, our finding might shed a new light on exploring the strategies for the treatment of NSCLC.

show abstract

The cyclin‐dependent kinase inhibitor p27^Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

et al. 2022

View full text Add to dashboard Cite

Edited by Ivan Sadowski p27 Kip1 functions to coordinate cell cycle progression through the inhibition of cyclin-dependent kinase (CDK) complexes. p27 Kip1 also exerts distinct activities beyond CDK-inhibition, including functioning as a transcriptional regulator. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with diverse biological roles. The regulatory inputs that control AhRmediated transcriptional responses are an active area of investigation. AhR was previously established as a direct regulator of p27 Kip1 transcription. Here, we report the physical interaction of AhR and p27 Kip1 and show that p27 Kip1 expression negatively regulates AhR-mediated transcription. p27 Kip1 knockout cells display increased AhR nuclear localisation and significantly higher expression of AhR target genes. This work thus identifies new regulatory cross-talk between p27 Kip1 and AhR.

show abstract

p27 controls Ragulator and mTOR activity in amino acid-deprived cells to regulate the autophagy–lysosomal pathway and coordinate cell cycle and cell growth

Cited by 89 publications

References 75 publications

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

Knockdown of SNORA47 Inhibits the Tumorigenesis of NSCLC via Mediation of PI3K/Akt Signaling Pathway

The cyclin‐dependent kinase inhibitor p27^Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

Contact Info

Product

Resources

About

p27 controls Ragulator and mTOR activity in amino acid-deprived cells to regulate the autophagy–lysosomal pathway and coordinate cell cycle and cell growth

Cited by 89 publications

References 75 publications

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

Knockdown of SNORA47 Inhibits the Tumorigenesis of NSCLC via Mediation of PI3K/Akt Signaling Pathway

The cyclin‐dependent kinase inhibitor p27Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

Contact Info

Product

Resources

About

The cyclin‐dependent kinase inhibitor p27^Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity