TSC1/TSC2 inactivation inhibits AKT through mTORC1‐dependent up‐regulation of STAT3‐PTEN cascade
Abstract
Aberrant activation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss or inactivation of TSC1/TSC2 protein complex, leads to negative feedback inhibition of Akt. The exact mechanisms of this process are still not fully understood. Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process. We demonstrate that STAT3 promotes the transcription of PTEN by directly binding on the PTEN promoter. Elevated PTEN then inhibits the proliferation of Tsc1(-/-) or Tsc2(-/-) cells through down-regulation of Akt signaling. Activation of PTEN in this pathway may thus serve as a protective mechanism against hyper-activated mTORC1 mediated tumorigenesis and contribute to the benign nature of tumors caused by loss of either TSC1 or TSC2.
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Inactivation of the TSC1/TSC2 protein complex leads to aberrant activation of mTORC1, resulting in inhibition of Akt.
“Inactivation of the TSC1/TSC2 protein complex leads to an aberrant activation of mTORC1, resulting in an inhibition of Akt, 45”
Activation of the AKT1 gene promotes mTORC1 activity by phosphorylating and inhibiting the TSC1/2 complex, leading to a downstream cascade of effects on protein synthesis and neuronal excitability.
“while activation of the AKT1 gene promotes mTORC1 activity by phosphorylating and inhibiting the TSC1/2 complex, leading to a downstream cascade of effects on protein synthesis and neuronal excitability. 45”
TSC1 acts as a negative regulator of the mTORC1 complex by inhibiting it.
“TSC1 acts as a negative regulator of the mTORC1 complex by inhibiting it”
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References 31 · Cited by 25
- Authors
- Zha, X., Hu, Z., He, S., Wang, F., Shen, H., & Zhang, H.
- Affiliations
- Anhui Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Sun Yat-sen University (CN)
- Corresponding author
- Zha, Xiaojun
- Shen, Huangxuan
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 313
- Issue
- 2
- Pages
- 211-217
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2131904231
- Cited by
- 25
- References
- 31
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- TSC1, TSC2, mTORC1, Akt signaling, STAT3, PTEN, negative feedback regulation, tumor suppressor, cell proliferation, carcinogenesis
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Cell Transformation, Neoplastic, Cells, Cultured, Humans, Promoter Regions, Genetic, Proteins, Signal Transduction, Down-Regulation, Up-Regulation, Tumor Suppressor Proteins, Multiprotein Complexes, Cell Proliferation, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, TOR Serine-Threonine Kinases
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