2016
DOI: 10.1016/j.bbamcr.2016.03.009
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Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2 -null cell survival

Abstract: Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin tr… Show more

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Cited by 19 publications
(19 citation statements)
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“…The black line with an arrow represents the activation process and the red line with a rectangular bar at the end represents the suppression process. (Ballif et al, 2005;Campos et al, 2016;Corradetti, Inoki, Bardeesy, DePinho, & Guan, 2004;Ellisen, 2005;Gao et al, 2015;Hoxhaj et al, 2017;Huang, Wu, Wu, & Manning, 2009;Inoki et al, 2006;Inoki, Li, Zhu, Wu, & Guan, 2002;Natarajan, Trivedi-Vyas, & Wairkar, 2013;Sofer, Lei, Johannessen, & Ellisen, 2005;Zhang et al, 2003) variants have been sought in DNA from blood. However, when the analysis is negative and the patient has a clinical diagnosis but a mild phenotype, clinicians should consider mosaicism and may try to analyze a different tissue, such as buccal smear, skin biopsy of a facial angiofibroma or of a hypomelanotic macule, brain or renal tissue if surgery is going to be performed.…”
Section: Mosaicism and No Mutation Identifiedmentioning
confidence: 99%
“…The black line with an arrow represents the activation process and the red line with a rectangular bar at the end represents the suppression process. (Ballif et al, 2005;Campos et al, 2016;Corradetti, Inoki, Bardeesy, DePinho, & Guan, 2004;Ellisen, 2005;Gao et al, 2015;Hoxhaj et al, 2017;Huang, Wu, Wu, & Manning, 2009;Inoki et al, 2006;Inoki, Li, Zhu, Wu, & Guan, 2002;Natarajan, Trivedi-Vyas, & Wairkar, 2013;Sofer, Lei, Johannessen, & Ellisen, 2005;Zhang et al, 2003) variants have been sought in DNA from blood. However, when the analysis is negative and the patient has a clinical diagnosis but a mild phenotype, clinicians should consider mosaicism and may try to analyze a different tissue, such as buccal smear, skin biopsy of a facial angiofibroma or of a hypomelanotic macule, brain or renal tissue if surgery is going to be performed.…”
Section: Mosaicism and No Mutation Identifiedmentioning
confidence: 99%
“…p27 was previously found to promote survival under serum and glucose starvation 14, 36, 37 . Surprisingly, p27 had opposite effects on survival upon glucose or aa starvation.…”
Section: Resultsmentioning
confidence: 95%
“…Cytoplasmic p27 was recently described as a positive regulator of basal and starvation-induced autophagy and to protect cells in conditions of metabolic stress from apoptosis by promoting autophagy 14, 3337 . Glucose or serum deprivation activates the energy/nutrient sensing kinases LKB1 and AMPK, in turn AMPK phosphorylates p27 on S83, T170 and T198, causing its stabilization and cytoplasmic retention 14, 36, 38 .…”
Section: Introductionmentioning
confidence: 99%
“…Inoki et al 27 , reported that AMPK activation is involved mTORC1-dependent inhibition of autophagy via phosphorylation and activation of the tuberous sclerosis complex 2 (TSC2) and also in the regulation of rapamycin-induced autophagy in TSC2-null cells through the dependence on p27 activity. 28 However, AMPK activation showed partly induced phosphorylation of ULK1 at Ser555 in the 5637 and HT1376 cells by the inhibition of mTOR phosphorylation and did not inhibit the phosphorylation of ULK1 at Ser757. Induction of autophagy was likely not absolute in the URCa cells treated with rapamycin in spite of the induction of AMPK activation by rapamycin.…”
Section: Discussionmentioning
confidence: 90%
“…We found that phosphorylation of AMPKα in the 5637 and HT1376 cells was highly induced by rapamycin treatment, but was induced to a much lesser degree in the 253J and T24 cells (Figure B). Inoki et al, reported that AMPK activation is involved mTORC1‐dependent inhibition of autophagy via phosphorylation and activation of the tuberous sclerosis complex 2 (TSC2) and also in the regulation of rapamycin‐induced autophagy in TSC2‐null cells through the dependence on p27 activity . However, AMPK activation showed partly induced phosphorylation of ULK1 at Ser555 in the 5637 and HT1376 cells by the inhibition of mTOR phosphorylation and did not inhibit the phosphorylation of ULK1 at Ser757.…”
Section: Discussionmentioning
confidence: 99%