TSC2 deficiency increases PTEN via HIF1alpha.
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.
Mahimainathan
Lenin
L
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Ghosh-Choudhury
Nandini
N
Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas 78229; Department of Pathology, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Venkatesan
Balachandar
B
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Das
Falguni
F
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Mandal
Chandi C
CC
Department of Pathology, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Dey
Nirmalya
N
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
Habib
Samy L
SL
Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas 78229; Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas 78229.
Kasinath
Balakuntalam S
BS
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900; Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas 78229.
Abboud
Hanna E
HE
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900; Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas 78229.
Ghosh Choudhury
Goutam
G
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900; Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas 78229; Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas 78229. Electronic address: choudhuryg@uthscsa.edu.
D018207:Angiomyolipoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse