TY - JOUR
T1 - TSC2 deficiency increases PTEN via HIF1α
AU - Mahimainathan, Lenin
AU - Ghosh-Choudhury, Nandini
AU - Venkatesan, Balachandar
AU - Das, Falguni
AU - Mandal, Chandi C.
AU - Dey, Nirmalya
AU - Habib, Samy L.
AU - Kasinath, Balakuntalam S.
AU - Abboud, Hanna E.
AU - Choudhury, Goutam Ghosh
PY - 2009/10/9
Y1 - 2009/10/9
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.028860
DO - 10.1074/jbc.M109.028860
M3 - Article
C2 - 19648120
AN - SCOPUS:70350463564
SN - 0021-9258
VL - 284
SP - 27790
EP - 27798
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -