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| Status |
Public on Apr 14, 2020 |
| Title |
mTORC1 feedback to AKT modulates MiT/TFE-driven lysosomal biogenesis and EGFR degradation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
MiT/TFE transcriptional activity controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. Some tumors bypass this regulatory circuit via genetic alterations that drive MiT/TFE expression and activity; however, the mechanisms by which cells with intact or constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we find that epidermal Tsc1 deletion results in a wavy hair phenotype due to increased EGFR degradation. Unexpectedly, constitutive mTORC1 activation increases lysosomal content via up-regulated expression and activity of MiT/TFEs, while genetic or prolonged pharmacologic mTORC1 inactivation has the reverse effect. This paradoxical up-regulation of lysosomal biogenesis by mTORC1 is mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE proteasomal degradation. These data suggest that oncogenic feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.
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| Overall design |
We performed microarray-based differential expression analysis of E18.5 epidermis from wild-type (3 biological replicates) and Rptor cKO (3 biological replicates) epidermal RNA samples and performed Gene Set Enrichment Analysis, GSEA to evaluate whether a lysosomal gene signature panel (consisting of 360 lysosomal gene transcripts from the Mouse Lysosome Gene Database (mLGDB; http://lysosome.unipg.it/mouse.php) was significantly negatively enriched in Rptor cKO epidermis.
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| Contributor(s) |
Lotan TL, Asrani K, Sood A, Murali S, Na C, Kaur H, Khan Z, Lam B, Phatak P, Noë M, Anchoori RK, Talbot CC Jr, Smith B, Skaro M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jan 07, 2019 |
| Last update date |
Apr 16, 2020 |
| Contact name |
KAUSHAL VIJAY ASRANI |
| E-mail(s) |
[email protected]
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| Phone |
4109268061
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| Organization name |
JOHNS HOPKINS MEDICINE
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| Street address |
1550 ORLEANS
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| City |
BALTIMORE |
| State/province |
MD |
| ZIP/Postal code |
21231 |
| Country |
USA |
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| Platforms (1) |
| GPL20775 |
[MTA-1_0] Affymetrix Mouse Transcriptome Array 1.0 [transcript (gene) CSV version] |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA513331 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE124754_RAW.tar |
140.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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