TSC2 deficiency increases PTEN via HIF1α

Lenin Mahimainathan, Nandini Ghosh-Choudhury, Balachandar Venkatesan, Falguni Das, Chandi C. Mandal, Nirmalya Dey, Samy L. Habib, Balakuntalam S. Kasinath, Hanna E. Abboud, Goutam Ghosh Choudhury

Research output: Contribution to journalArticle

19 Scopus citations

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 HIF1α 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 HIF1α and PTEN in renal angiomyolipomas from TSC patients. Our results reveal a unique function of HIF1α 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.

Original languageEnglish (US)
Pages (from-to)27790-27798
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number41
DOIs
StatePublished - Oct 9 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mahimainathan, L., Ghosh-Choudhury, N., Venkatesan, B., Das, F., Mandal, C. C., Dey, N., Habib, S. L., Kasinath, B. S., Abboud, H. E., & Choudhury, G. G. (2009). TSC2 deficiency increases PTEN via HIF1α. Journal of Biological Chemistry, 284(41), 27790-27798. https://doi.org/10.1074/jbc.M109.028860