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Gene Review

Thor  -  CG8846 gene product from transcript CG8846-RA

Drosophila melanogaster

Synonyms: 153432_at, 43-BP, 4E-BP, 4E-BP1, 4EBP, ...
 
 
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Disease relevance of Thor

 

High impact information on Thor

  • The Drosophila insulin-like receptor (dINR) pathway incorporates 4E-BP resistant cellular internal ribosome entry site (IRES) containing mRNAs, to functionally couple transcriptional activation with differential translational control in a cell that is otherwise translationally repressed by 4E-BP [2].
  • 4E-BP activity is controlled by TOR (Target of Rapamycin) [3].
  • eIF4E, the mRNA 5' cap-binding protein, is regulated by its binding protein (4E-BP), a downstream target of phosphatidylinositol-3-OH kinase [PI(3)K] signaling [4].
  • We show that ectopic expression of d4E-BP in dFOXO-null flies restores oxidative stress resistance to control levels [4].
  • Thus, d4E-BP is an important downstream effector of a dFOXO phenotype, and regulation of translation by eIF4E is vital during environmental stress [4].
 

Biological context of Thor

  • Drosophila Thor participates in host immune defense and connects a translational regulator with innate immunity [1].
  • The Thor promoter has the canonical NFkappaB and associated GATA recognition sequences that have been shown to be essential for immune induction, as well as other sequences commonly found for Drosophila immune response genes, including interferon-related regulatory sequences [1].
  • Analysis of d4E-BP phosphorylation using site-directed mutagenesis and isoelectric focusing-sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that the regulatory interplay between Thr37 and Thr46 of d4E-BP is conserved in flies and that phosphorylation of Thr46 is the major phosphorylation event that regulates d4E-BP activity [5].
  • Our results support a role for d4E-BP as an effector of cell growth [6].
  • Ectopic expression of a highly active d4E-BP mutant in wing-imaginal discs causes a reduction of wing size, brought about by a decrease in cell size and number [6].
 

Associations of Thor with chemical compounds

  • Expression of d4E-BP in the eye and wing together with PI(3)K or dAkt1, the serine/threonine kinase downstream of PI(3)K, resulted in suppression of the growth phenotype elicited by these kinases [6].
  • To overcome this protective mechanism, we introduced alanine substitutions at four phosphorylation/inactivation sites in 4EBP1 to constitutively activate a 4EBP mu to block eIF4E [7].
 

Regulatory relationships of Thor

  • The Drosophila forkhead transcription factor (dFOXO) activates d4E-BP transcription [4].
 

Other interactions of Thor

  • The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila [6].
  • Mutant dFOXO lacking dAkt phosphorylation sites no longer responds to insulin inhibition, remains in the nucleus, and is constitutively active. dFOXO activation in S2 cells induces growth arrest and activates two key players of the dInR/dPI3K/dAkt pathway: the translational regulator d4EBP and the dInR itself [8].
 

Analytical, diagnostic and therapeutic context of Thor

  • By microarray analysis and subsequent genetic validation, we have identified d4E-BP, which encodes a translation inhibitor, as a relevant dFOXO target gene [9].
  • 4E-BP has been studied extensively in cell culture; however, the biological role of 4E-BP in developing organisms is unclear to date [3].

References

  1. Drosophila Thor participates in host immune defense and connects a translational regulator with innate immunity. Bernal, A., Kimbrell, D.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  2. IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback. Marr, M.T., D'Alessio, J.A., Puig, O., Tjian, R. Genes Dev. (2007) [Pubmed]
  3. 4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. Teleman, A.A., Chen, Y.W., Cohen, S.M. Genes Dev. (2005) [Pubmed]
  4. Starvation and oxidative stress resistance in Drosophila are mediated through the eIF4E-binding protein, d4E-BP. Tettweiler, G., Miron, M., Jenkins, M., Sonenberg, N., Lasko, P.F. Genes Dev. (2005) [Pubmed]
  5. Signaling from Akt to FRAP/TOR targets both 4E-BP and S6K in Drosophila melanogaster. Miron, M., Lasko, P., Sonenberg, N. Mol. Cell. Biol. (2003) [Pubmed]
  6. The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila. Miron, M., Verdú, J., Lachance, P.E., Birnbaum, M.J., Lasko, P.F., Sonenberg, N. Nat. Cell Biol. (2001) [Pubmed]
  7. Activated eIF4E-binding protein slows G1 progression and blocks transformation by c-myc without inhibiting cell growth. Lynch, M., Fitzgerald, C., Johnston, K.A., Wang, S., Schmidt, E.V. J. Biol. Chem. (2004) [Pubmed]
  8. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Puig, O., Marr, M.T., Ruhf, M.L., Tjian, R. Genes Dev. (2003) [Pubmed]
  9. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. Jünger, M.A., Rintelen, F., Stocker, H., Wasserman, J.D., Végh, M., Radimerski, T., Greenberg, M.E., Hafen, E. J. Biol. (2003) [Pubmed]
 
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