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Gene Review

Cux1  -  cut-like homeobox 1

Mus musculus

Synonyms: AA407197, CCAAT displacement protein, CDP, Cutl1, Cux, ...
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Disease relevance of Cutl1


High impact information on Cutl1

  • The mammalian Cutl1 gene codes for the CCAAT displacement protein (CDP), which has been implicated as a transcriptional repressor in diverse processes such as terminal differentiation, cell cycle progression, and the control of nuclear matrix attachment regions [5].
  • The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle [5].
  • The inner root sheath (IRS) is reduced, and the transcription of Sonic hedgehog and IRS-specific genes is deregulated in Cutl1 mutant hair follicles, consistent with the specific expression of Cutl1 in the progenitors and cell lineages of the IRS [5].
  • We also provide genetic evidence to show that Rnx and Phox2 proteins may function independently to specify the (nor)adrenergic phenotype [6].
  • We show here that cathepsin L functions in the regulation of cell cycle progression through proteolytic processing of the CDP/Cux transcription factor [7].

Biological context of Cutl1

  • The mouse homeodomain protein Phox2 regulates Ncam promoter activity in concert with Cux/CDP and is a putative determinant of neurotransmitter phenotype [8].
  • In transient transfection experiments, Cux was found to be a strong inhibitor of Ncam promoter activity, and this inhibition could be relieved by simultaneously overexpressing Phox2 [8].
  • Proteolytic processing of CDP/Cux by cathepsin L generates the CDP/Cux p110 isoform at the beginning of S phase [9].
  • CDP/Cux p110 makes stable interactions with DNA during S phase but is inhibited in G2 following the phosphorylation of serine 1237 by cyclin A/Cdk1 [9].
  • Altogether our results help explain why the DNA binding activity of CDP/Cux p110 is maximal during S phase and decreases in G2 phase [9].

Anatomical context of Cutl1


Associations of Cutl1 with chemical compounds

  • We conclude that the presence of antisense Cux-1 ODNs does not block nephron induction, but results instead in increased apoptosis [13].
  • To further evaluate the role of Cux-1 in mammalian kidney development, organotypic cultures of embryonic mouse kidney were incubated with phosphorothioate-coupled antisense Cux-1 oligonucleotides (ODNs) in the presence of cationic liposomes [13].
  • We designed a targeting construct to replace the first cut repeat with a neomycin resistance cassette, introducing a nonsense mutation after position 1319 of the 4.5-kb reading frame of Cux/CDP [11].
  • In contrast, CsA-treated Cux-1 transgenic kidney cultures were not growth inhibited, but showed high levels of cell proliferation in the nephrogenic zone [14].
  • In precursors cells, Cux-1 immunoreactivity is weak and diffuse in the cytoplasm and nucleus of ventricular zone (VZ) cells, whereas it is nuclear in the majority of bromodeoxyuridine (BrdU)-positive subventricular zone (SVZ) dividing cells, suggesting that Cux-1 function is first activated in SVZ cells [15].

Physical interactions of Cutl1

  • In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor [16].

Regulatory relationships of Cutl1

  • Furthermore, Cux-1 was significantly up-regulated in the rat kidney epithelial cell line RKE expressing a constitutively active Notch 1, and this finding was associated with a reduction of p27 [17].
  • These results suggest that Cux-1 regulates cell proliferation during early nephrogenesis by inhibiting expression of p27 [2].
  • Cux/CDP homeoprotein is a component of NF-muNR and represses the immunoglobulin heavy chain intronic enhancer by antagonizing the bright transcription activator [18].
  • While Cux1 is widely expressed in mouse embryos particularly in the nephrogenic and urogenital systems, in contrast the early embryonic expression of Cux2 has not been characterized [19].

Other interactions of Cutl1

  • Here we identify two mouse homeodomain proteins that bind to an upstream regulatory element in the Ncam promoter: Cux, related to Drosophila cut and human CDP, and Phox2, a novel protein with a homeodomain related to that of the Drosophila paired gene [8].
  • We did not observe an N-terminally processed Cux2 isoform equivalent to the Cux1 p110 isoform [20].
  • In late stages of cystogenesis, Cux-1 and p21 colocalized in cyst lining cells, which also showed a high incidence of apoptosis [4].
  • In Pkd1 null mice, ectopic expression of Cux-1 is associated with increased cell proliferation [4].
  • Moreover, in CsA-treated Cux-1 transgenic kidney cultures, p27 was not expressed in the nephrogenic zone, but only up-regulated in maturing glomeruli and tubules [14].

Analytical, diagnostic and therapeutic context of Cutl1


  1. Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice. Sinclair, A.M., Lee, J.A., Goldstein, A., Xing, D., Liu, S., Ju, R., Tucker, P.W., Neufeld, E.J., Scheuermann, R.H. Blood (2001) [Pubmed]
  2. Deregulated expression of the homeobox gene Cux-1 in transgenic mice results in downregulation of p27(kip1) expression during nephrogenesis, glomerular abnormalities, and multiorgan hyperplasia. Ledford, A.W., Brantley, J.G., Kemeny, G., Foreman, T.L., Quaggin, S.E., Igarashi, P., Oberhaus, S.M., Rodova, M., Calvet, J.P., Vanden Heuvel, G.B. Dev. Biol. (2002) [Pubmed]
  3. Cux-1 transgenic mice develop glomerulosclerosis and interstitial fibrosis. Brantley, J.G., Sharma, M., Alcalay, N.I., Heuvel, G.B. Kidney Int. (2003) [Pubmed]
  4. Differential expression of Cux-1 and p21 in polycystic kidneys from Pkd1 null and cpk mice. Sharma, M., Brantley, J.G., Alcalay, N.I., Zhou, J., Heystek, E., Maser, R.L., Vanden Heuvel, G.B. Kidney Int. (2005) [Pubmed]
  5. The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle. Ellis, T., Gambardella, L., Horcher, M., Tschanz, S., Capol, J., Bertram, P., Jochum, W., Barrandon, Y., Busslinger, M. Genes Dev. (2001) [Pubmed]
  6. Formation of brainstem (nor)adrenergic centers and first-order relay visceral sensory neurons is dependent on homeodomain protein Rnx/Tlx3. Qian, Y., Fritzsch, B., Shirasawa, S., Chen, C.L., Choi, Y., Ma, Q. Genes Dev. (2001) [Pubmed]
  7. A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor. Goulet, B., Baruch, A., Moon, N.S., Poirier, M., Sansregret, L.L., Erickson, A., Bogyo, M., Nepveu, A. Mol. Cell (2004) [Pubmed]
  8. The mouse homeodomain protein Phox2 regulates Ncam promoter activity in concert with Cux/CDP and is a putative determinant of neurotransmitter phenotype. Valarché, I., Tissier-Seta, J.P., Hirsch, M.R., Martinez, S., Goridis, C., Brunet, J.F. Development (1993) [Pubmed]
  9. Differential regulation of CDP/Cux p110 by cyclin A/Cdk2 and cyclin A/Cdk1. Santaguida, M., Nepveu, A. J. Biol. Chem. (2005) [Pubmed]
  10. Negative transcriptional modulation and silencing of the bi-exonic Rnf35 gene in the preimplantation embryo. Binding of the CCAAT-displacement protein/Cux to the untranslated exon 1 sequence. Huang, C.J., Chang, J.G., Wu, S.C., Choo, K.B. J. Biol. Chem. (2005) [Pubmed]
  11. Hair defects and pup loss in mice with targeted deletion of the first cut repeat domain of the Cux/CDP homeoprotein gene. Tufarelli, C., Fujiwara, Y., Zappulla, D.C., Neufeld, E.J. Dev. Biol. (1998) [Pubmed]
  12. Expression of a cut-related homeobox gene in developing and polycystic mouse kidney. Vanden Heuvel, G.B., Bodmer, R., McConnell, K.R., Nagami, G.T., Igarashi, P. Kidney Int. (1996) [Pubmed]
  13. Antisense oligonucleotides to Cux-1, a Cut-related homeobox gene, cause increased apoptosis in mouse embryonic kidney cultures. Quaggin, S.E., Yeger, H., Igarashi, P. J. Clin. Invest. (1997) [Pubmed]
  14. Ectopic expression of the homeobox gene Cux-1 rescues calcineurin inhibition in mouse embryonic kidney cultures. Alcalay, N.I., Brantley, J.G., Sharma, M., Gooch, J.L., Vanden Heuvel, G.B. Dev. Dyn. (2007) [Pubmed]
  15. Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex. Nieto, M., Monuki, E.S., Tang, H., Imitola, J., Haubst, N., Khoury, S.J., Cunningham, J., Gotz, M., Walsh, C.A. J. Comp. Neurol. (2004) [Pubmed]
  16. A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. Jing, H., Yen, J.H., Ganea, D. J. Biol. Chem. (2004) [Pubmed]
  17. Coexpression of Cux-1 and Notch signaling pathway components during kidney development. Sharma, M., Fopma, A., Brantley, J.G., Vanden Heuvel, G.B. Dev. Dyn. (2004) [Pubmed]
  18. Cux/CDP homeoprotein is a component of NF-muNR and represses the immunoglobulin heavy chain intronic enhancer by antagonizing the bright transcription activator. Wang, Z., Goldstein, A., Zong, R.T., Lin, D., Neufeld, E.J., Scheuermann, R.H., Tucker, P.W. Mol. Cell. Biol. (1999) [Pubmed]
  19. Dynamic expression of murine Cux2 in craniofacial, limb, urogenital and neuronal primordia. Iulianella, A., Vanden Heuvel, G., Trainor, P. Gene Expr. Patterns (2003) [Pubmed]
  20. Biochemical characterization of the mammalian Cux2 protein. Gingras, H., Cases, O., Krasilnikova, M., Bérubé, G., Nepveu, A. Gene (2005) [Pubmed]
  21. CDP/Cux stimulates transcription from the DNA polymerase alpha gene promoter. Truscott, M., Raynal, L., Premdas, P., Goulet, B., Leduy, L., Bérubé, G., Nepveu, A. Mol. Cell. Biol. (2003) [Pubmed]
  22. Characterization of proteins of chicken infectious anemia virus with monoclonal antibodies. Chandratilleke, D., O'Connell, P., Schat, K.A. Avian Dis. (1991) [Pubmed]
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