Disease relevance of Cutl1

• Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice [1].
• Cux-1 is highly expressed in cyst epithelium of polycystic kidneys from C57BL/6J-cpk/cpk mice, but not in kidneys isolated from age-matched phenotypically normal littermates [2].
• These results suggest that expression of Cux-1 is sufficient to induce the early events of mesangioproliferative glomerulonephritis [3].
• Cux-1 transgenic mice develop glomerulosclerosis and interstitial fibrosis [3].
• Previously, we observed that Cux-1 is deregulated in cystic kidneys from cpk mice [4].

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

• All Phox2-expressing components of the peripheral nervous system are at least transiently adrenergic or noradrenergic [8].
• 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 [10].
• Homozygous mutant mice, designated Cux/CDPDeltaCR1, display a phenotype characterized by curly vibrissae and wavy hair [11].
• Within the metanephros, Cux-1 was expressed in the nephrogenic zone including both mesenchymal cells (uninduced and condensed mesenchyme) and epithelial cells (ureteric buds, renal vesicles, S-shaped bodies) [12].
• CONCLUSION: These observations indicate that increased expression of Cux-1 in mesangial cells results in cell proliferation and mesangial expansion [3].

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

• Electrophoretic mobility shift assays demonstrated that the 3'-half of DER (DER2) was targeted by the repressor CCAAT-displacement protein (CDP)/Cux [10].
• Mice constitutively expressing Cux-1 developed multiorgan hyperplasia and organomegaly, but not an overall increase in body size [2].
• We examined the expression of a murine cut homologue (named Cux-1) in the developing mouse using Northern blot analysis and in situ hybridization [12].
• Chromatin immunoprecipitation (ChIP) assays revealed that CDP/Cux was associated with the DNA pol alpha gene promoter specifically in the S phase [21].
• All MAbs reacted in a direct enzyme-linked immunosorbent assay with Cux-1 antigen treated with 0.5% sodium dodecyl sulfate followed by extraction with chloroform, but not with MSB1 cells infected with Cux-1 or chloroform-extracts of these cells [22].

References