Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling
| Autor: | Jacques Montagne, Thomas Radimerski, George Thomas, Maja Hemmings-Mieszczak |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Down-Regulation P70-S6 Kinase 1 Genes Insect Protein Serine-Threonine Kinases medicine.disease_cause Eye Phosphatidylinositol 3-Kinases Research Communication Phosphatidylinositol Phosphates Tuberous Sclerosis Proto-Oncogene Proteins Genetics medicine PTEN Animals Wings Animal Genes Tumor Suppressor RNA Double-Stranded Mutation biology Effector Ribosomal Protein S6 Kinases Tumor Suppressor Proteins PTEN Phosphohydrolase Protein-Tyrosine Kinases biology.organism_classification Molecular biology Phosphoric Monoester Hydrolases Enzyme Activation medicine.anatomical_structure Drosophila melanogaster biology.protein Genes Lethal TSC1 TSC2 Signal transduction Proto-Oncogene Proteins c-akt Cell Division Developmental Biology Signal Transduction |
| Zdroj: | Genesdevelopment. 16(20) |
| ISSN: | 0890-9369 |
| Popis: | Hereditary cancers have revealed the existence of a number of tumor suppressor genes that function to control cell proliferation and maintain normal tissue homeostasis (Macleod 2000). Two tumor suppressors have been implicated in the PI3K-signaling pathway, PTEN (Cantley and Neel 1999) and more recently, a complex composed of two proteins, hamartin (TSC1) and tuberin (TSC2; Montagne et al. 2001). The lipid phosphatase PTEN, which constrains PI3K signaling by dephosphorylating its product phosphatidylinositol 3,4,5-trisphosphate (PIP3), is found mutated in a number of cancers (Cantley and Neel 1999). Mutations in either TSC1 or TSC2 are associated with widespread medically distinct tumors of the brain, eyes, skin, heart, lungs, and kidneys (Young and Povey 1998). TSC1 and TSC2 contain putative coiled-coil domains, with TSC1 having a predicted transmembrane domain and TSC2 a region similar to that of small-GTPase-activating protein (GAP) domains (Montagne et al. 2001). Although little is known concerning the growth regulatory targets of TSC1 and TSC2, genetic studies in Drosophila (Potter et al. 2001; Tapon et al. 2001) have led recently to the hypothesis that dTsc1/2 acts as a negative effector of dS6K or of a dS6K target (Potter et al. 2001). In these models, dS6K was placed as a downstream effector of dPI3K, via dPKB (Potter et al. 2001). However, dS6K and dPI3K/dPKB appear to reside on parallel growth-promoting pathways rather than functioning in a linear-signaling cascade (Radimerski et al. 2002). Seemingly consistent with these findings, in Drosophila devoid of dPTEN, dPKB appears to be the sole critical target activated by elevated PIP3 levels (Stocker et al. 2002). Here, we use double-stranded RNA mediated interference (dsRNAi) in Drosophila Kc167 cultured cells to demonstrate that dTsc1/2 acts to suppress dS6K activation, whereas dPTEN negatively regulates dPKB activation but has little effect on dS6K activity. Similar findings are obtained in second instar larvae deficient for either dTsc or dPTEN function, whereas overexpression of either dTsc1/2 or dPTEN in second instar larvae selectively inhibits dS6K or dPKB activity, respectively. In addition, loss of dTsc1/2 function in Kc167 cells or in larvae also leads to suppression of dPKB activity, an effect that is relieved by loss of dS6K. More strikingly, we demonstrate that a relative subtle pharmacological or genetic reduction in dS6K signaling is sufficient to rescue larval lethality associated with loss of dTsc function. These latter findings strongly suggest that the S6K pathway is a promising target for pharmaceutical intervention in tuberous sclerosis treatment. |
| Databáze: | OpenAIRE |
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