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Gene Review

ci  -  cubitus interruptus

Drosophila melanogaster

Synonyms: CG2125, CI, CID, Ce, Ci, ...
 
 
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Disease relevance of ci

  • Haploinsufficiency for the ci-related transcription factor Gli3 causes phenotypic changes in mice (known as 'extra-toes) and humans (Greig's cephalopolysyndactyly syndrome) that have similarities to Rubinstein-Taybi syndrome [1].
  • In vertebrates, three Ci-related transcription factors (glioblastoma gene products (GLIs) 1, 2, and 3) were identified, but their functional difference in Hh signal transduction is unknown [2].
  • Second, overexpression of Cubitus interruptus causes the suppression of denticles (as Wingless does) in absence of Wingless activity in the anterior trunk [3].
 

High impact information on ci

 

Biological context of ci

  • These mutant proteins are unable to transactivate a reporter gene regulated by ci binding sites and have a lower dCBP-stimulated activity than wild-type CI [8].
  • This model is consistent with genetic data demonstrating that Su(fu) is not required for Hh signal transduction proper and with the elaborate genetic interactions observed among Su(fu), fu, cos2, and ci [9].
  • Coincidentally, pan and ci are adjacent genes on the fourth chromosome in a head-to-head orientation [10].
  • Other loss-of-function en alleles also enhance the ci phenotype, with the en lethal alleles (and deletions) showing the strongest effect, while the homozygous viable en alleles show weaker enhancement [11].
  • As a double heterozygote, it also enhances the ci wing vein phenotype of the dominant alleles ciW and ciCe2, but not ciD [11].
 

Anatomical context of ci

  • We propose that the association of the Cos2 protein complex with Smo at the plasma membrane controls the stability of the complex and allows Ci activation, eliciting its nuclear translocation [12].
  • Specifically, we show that the mechanism by which Hh signaling controls initiation of photoreceptor differentiation is to alleviate repression of eya and decapentaplegic (dpp) expression by the zinc-finger transcription factor Cubitus interruptus (Ci(rep)) [13].
  • Fu, Cos-2 and Ci are co-associated in vivo in large complexes that are bound to microtubules in a Hh-dependent manner [6,7] [14].
  • We show that the Drosophila Schneider 2 (S2) cell line has the potential to transduce the Hh-triggered intracellular signals, leading to the activation of target gene expression, when a transcription factor, Cubitus interruptus (Ci), is provided exogenously [15].
  • Consequently, the transcription of CI-dependent genes leads to stem cell proliferation [16].
 

Associations of ci with chemical compounds

 

Physical interactions of ci

 

Enzymatic interactions of ci

  • Here we demonstrate that the PKA pathway antagonizes the hh pathway by phosphorylating CI [26].
  • We propose that Cos2 recruits multiple kinases to efficiently phosphorylate Ci and that Hh inhibits Ci phosphorylation by specifically interfering with kinase recruitment [27].
 

Regulatory relationships of ci

  • It is now shown that anterior cells lacking ci express hh and adopt posterior properties without expressing en [28].
  • The default activity of Ptc is to inhibit Ci function; when Ptc binds Hh, this inhibition is released and Ci can control wg transcription [29].
  • Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus [24].
  • These effects were all enhanced in a fu mutant context and were suppressed by cubitus interruptus (Ci) overexpression [30].
  • Mitotic clones induced at the beginning of the second larval instar do not cross the boundary between the engrailed-expressing and cubitus interruptus-expressing domains, indicating that these domains are true genetic compartments [31].
 

Other interactions of ci

  • Increased levels of Ci can induce the expression of the Hh target gene decapentaplegic (dpp) in a Hh-independent manner [28].
  • When expressed exogenously in embryos, the CI point mutants cannot activate endogenous wg expression [8].
  • Activity of this element depends on ptc, but it contains no consensus Ci-binding sites [29].
  • Engrailed and polyhomeotic maintain posterior cell identity through cubitus-interruptus regulation [32].
  • We have identified a 125 amino acid domain in the C-terminal part of Ci that mediates response to Cos2 inhibition [24].
 

Analytical, diagnostic and therapeutic context of ci

References

  1. Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling. Akimaru, H., Chen, Y., Dai, P., Hou, D.X., Nonaka, M., Smolik, S.M., Armstrong, S., Goodman, R.H., Ishii, S. Nature (1997) [Pubmed]
  2. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M., Ishii, S. J. Biol. Chem. (1999) [Pubmed]
  3. Cubitus interruptus acts to specify naked cuticle in the trunk of Drosophila embryos. Angelats, C., Gallet, A., Thérond, P., Fasano, L., Kerridge, S. Dev. Biol. (2002) [Pubmed]
  4. Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Price, M.A., Kalderon, D. Cell (2002) [Pubmed]
  5. Opposing transcriptional outputs of Hedgehog signaling and engrailed control compartmental cell sorting at the Drosophila A/P boundary. Dahmann, C., Basler, K. Cell (2000) [Pubmed]
  6. Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Méthot, N., Basler, K. Cell (1999) [Pubmed]
  7. Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Chen, C.H., von Kessler, D.P., Park, W., Wang, B., Ma, Y., Beachy, P.A. Cell (1999) [Pubmed]
  8. Cubitus interruptus requires Drosophila CREB-binding protein to activate wingless expression in the Drosophila embryo. Chen, Y., Goodman, R.H., Smolik, S.M. Mol. Cell. Biol. (2000) [Pubmed]
  9. Identification of a tetrameric hedgehog signaling complex. Stegman, M.A., Vallance, J.E., Elangovan, G., Sosinski, J., Cheng, Y., Robbins, D.J. J. Biol. Chem. (2000) [Pubmed]
  10. Drosophila ciD encodes a hybrid Pangolin/Cubitus interruptus protein that diverts the Wingless into the Hedgehog signaling pathway. Schweizer, L., Basler, K. Mech. Dev. (1998) [Pubmed]
  11. Engrailed gene dosage determines whether certain recessive cubitus interruptus alleles exhibit dominance of the adult wing phenotype in Drosophila. Locke, J., Hanna, S. Dev. Genet. (1996) [Pubmed]
  12. Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Ruel, L., Rodriguez, R., Gallet, A., Lavenant-Staccini, L., Thérond, P.P. Nat. Cell Biol. (2003) [Pubmed]
  13. Mechanism of hedgehog signaling during Drosophila eye development. Pappu, K.S., Chen, R., Middlebrooks, B.W., Woo, C., Heberlein, U., Mardon, G. Development (2003) [Pubmed]
  14. Suppressor of fused links fused and Cubitus interruptus on the hedgehog signalling pathway. Monnier, V., Dussillol, F., Alves, G., Lamour-Isnard, C., Plessis, A. Curr. Biol. (1998) [Pubmed]
  15. The fused protein kinase regulates Hedgehog-stimulated transcriptional activation in Drosophila Schneider 2 cells. Fukumoto, T., Watanabe-Fukunaga, R., Fujisawa, K., Nagata, S., Fukunaga, R. J. Biol. Chem. (2001) [Pubmed]
  16. The role of the hedgehog/patched signaling pathway in epithelial stem cell proliferation: from fly to human. Parisi, M.J., Lin, H. Cell Res. (1998) [Pubmed]
  17. Mutants of cubitus interruptus that are independent of PKA regulation are independent of hedgehog signaling. Chen, Y., Cardinaux, J.R., Goodman, R.H., Smolik, S.M. Development (1999) [Pubmed]
  18. Splitting the Hedgehog signal: sex and patterning in Drosophila. Horabin, J.I. Development (2005) [Pubmed]
  19. Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Robbins, D.J., Nybakken, K.E., Kobayashi, R., Sisson, J.C., Bishop, J.M., Thérond, P.P. Cell (1997) [Pubmed]
  20. Molecular cloning and functional expression of a serotonin receptor from Caenorhabditis elegans. Olde, B., McCombie, W.R. J. Mol. Neurosci. (1997) [Pubmed]
  21. The contributions of protein kinase A and smoothened phosphorylation to hedgehog signal transduction in Drosophila melanogaster. Zhou, Q., Apionishev, S., Kalderon, D. Genetics (2006) [Pubmed]
  22. Genetic evidence for a protein kinase A/cubitus interruptus complex that facilitates processing of cubitus interruptus in Drosophila. Kiger, J.A., O'Shea, C. Genetics (2001) [Pubmed]
  23. Modulation of Hedgehog target gene expression by the Fused serine-threonine kinase in wing imaginal discs. Alves, G., Limbourg-Bouchon, B., Tricoire, H., Brissard-Zahraoui, J., Lamour-Isnard, C., Busson, D. Mech. Dev. (1998) [Pubmed]
  24. Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Wang, G., Amanai, K., Wang, B., Jiang, J. Genes Dev. (2000) [Pubmed]
  25. The ciD mutation encodes a chimeric protein whose activity is regulated by Wingless signaling. Von Ohlen, T., Hooper, J.E. Dev. Biol. (1999) [Pubmed]
  26. Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus. Chen, Y., Gallaher, N., Goodman, R.H., Smolik, S.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  27. Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J., Jiang, J. Dev. Cell (2005) [Pubmed]
  28. Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus. Domínguez, M., Brunner, M., Hafen, E., Basler, K. Science (1996) [Pubmed]
  29. Expression of wingless in the Drosophila embryo: a conserved cis-acting element lacking conserved Ci-binding sites is required for patched-mediated repression. Lessing, D., Nusse, R. Development (1998) [Pubmed]
  30. Modulation of the Suppressor of fused protein regulates the Hedgehog signaling pathway in Drosophila embryo and imaginal discs. Dussillol-Godar, F., Brissard-Zahraoui, J., Limbourg-Bouchon, B., Boucher, D., Fouix, S., Lamour-Isnard, C., Plessis, A., Busson, D. Dev. Biol. (2006) [Pubmed]
  31. Compartmental organization of the Drosophila genital imaginal discs. Chen, E.H., Baker, B.S. Development (1997) [Pubmed]
  32. Engrailed and polyhomeotic maintain posterior cell identity through cubitus-interruptus regulation. Chanas, G., Lavrov, S., Iral, F., Cavalli, G., Maschat, F. Dev. Biol. (2004) [Pubmed]
  33. Genetic dissection of the Drosophila Cubitus interruptus signaling complex. Lefers, M.A., Wang, Q.T., Holmgren, R.A. Dev. Biol. (2001) [Pubmed]
 
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