A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.
Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.
Department Systems Neuroscience, Cajal Institute, CSIC, and CIBERNED, Madrid, Spain.
S
S
Fernández
Department Systems Neuroscience, Cajal Institute, CSIC, and CIBERNED, Madrid, Spain.
L
L
Genis
Department Systems Neuroscience, Cajal Institute, CSIC, and CIBERNED, Madrid, Spain.
I
I
Torres-Alemán
D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I; D017868:Cyclic AMP-Dependent Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human