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Updated: Jun 21, 2026

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.
Abstract:
Substantial evidence suggests roles of TSC2 and PTEN in the development of cancer predisposition syndromes. Loss of TSC2 results in benign tumors, neurological disorders, and angiomyolipomas. We found that PTEN mRNA and protein levels are elevated in Tsc2(-/-) mouse embryo fibroblasts with concomitant reduction in Akt phosphorylation. Reconstitution of TSC2 in Tsc2(-/-) mouse embryo fibroblasts decreases PTEN levels. Interestingly, increased HIF1alpha activity present in Tsc2 null cells is required for PTEN transcription and protein expression. We identified a canonical hypoxia-responsive element in the PTEN promoter, which regulates the transcription of this tumor suppressor protein in a TSC2-dependent manner. Finally, we demonstrate a positive correlation between expression of HIF1alpha and PTEN in renal angiomyolipomas from TSC patients. Our results reveal a unique function of HIF1alpha in up-regulation of PTEN and provide a new mechanism of reduced Akt phosphorylation in Tsc2 null cells. These data suggest that PTEN may safeguard against developing malignant tumors in patients with TSC deficiency.
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