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Related Experiment Video

Updated: Jun 21, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

TSC2 deficiency increases PTEN via HIF1alpha.

Lenin Mahimainathan1, Nandini Ghosh-Choudhury2, Balachandar Venkatesan1

  • 1Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.

The Journal of Biological Chemistry
|August 4, 2009
PubMed
Summary

Loss of TSC2 elevates PTEN levels via HIF1alpha, potentially safeguarding against malignant tumors in TSC patients. This study reveals a novel mechanism linking TSC2 deficiency to tumor suppression.

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Last Updated: Jun 21, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tuberous Sclerosis Complex (TSC) involves tumor predisposition syndromes linked to TSC2 and PTEN.
  • Loss of TSC2 function leads to benign tumors, neurological issues, and angiomyolipomas.

Purpose of the Study:

  • To investigate the molecular mechanisms linking TSC2 deficiency to PTEN expression.
  • To elucidate the role of HIF1alpha in regulating PTEN in Tsc2 null cells.
  • To explore the therapeutic potential of targeting the HIF1alpha-PTEN axis in TSC.

Main Methods:

  • Analysis of PTEN mRNA and protein levels in Tsc2(-/-) mouse embryo fibroblasts.
  • Investigation of Akt phosphorylation.
  • Assessment of HIF1alpha activity and its role in PTEN transcription.
  • Identification of a hypoxia-responsive element in the PTEN promoter.
  • Correlation analysis of HIF1alpha and PTEN expression in patient samples.

Main Results:

  • PTEN mRNA and protein levels were elevated in Tsc2(-/-) cells, with reduced Akt phosphorylation.
  • Reconstitution of TSC2 decreased PTEN levels.
  • Increased HIF1alpha activity in Tsc2 null cells was essential for PTEN transcription and expression.
  • A hypoxia-responsive element in the PTEN promoter was identified, regulating transcription in a TSC2-dependent manner.
  • A positive correlation between HIF1alpha and PTEN expression was observed in TSC patient renal angiomyolipomas.

Conclusions:

  • HIF1alpha plays a unique role in up-regulating PTEN expression.
  • A novel mechanism of reduced Akt phosphorylation in Tsc2 null cells involves HIF1alpha-mediated PTEN up-regulation.
  • PTEN may act as a tumor suppressor, protecting against malignant transformation in TSC deficiency.