CUX1 (cut-like homeobox 1)

2011-10-01   Benjamin Kühnemuth , Patrick Michl 

Department of Gastroenterology, Endocrinology, University of Marburg, Marburg, Germany





The human CUX1 gene is located on chromosome 7q22 (Scherer et al., 1993). It comprises 33 exons and spans 468 kb.
Five alternative splice variants have been identified. Most of the splicing sites are located in the regions downstream of exon 14 and 15 (Rong Zeng et al., 2000). Two alternative sites for transcript termination have been identified. Termination at UGA in exon 24 leads to production of CUX1 mRNA comprising exon 1-24. Elongation up to exon 33 results in alternative splicing and the production of CASP mRNA comprising exon 1-15 and 25-33 (Lievens et al., 1997; Rong Zeng et al., 2000).
The first transcriptional start site is located in exon 1 but transcription can be initiated at several sites in a 200 bp region upstream of exon 1 (Rong Zeng et al., 2000). Initiation within intron 20 leads to production of an mRNA coding for the shortened p75 isoform (Goulet et al., 2002).
Several putative translation initiation codons can be found in exon 1 but ATG at position 550 has been described as the predominant initiation site (Rong Zeng et al., 2000).


Atlas Image
Cux1 isoforms. The p75 isoform is the product of a shortened mRNA that is generated by the use of an alternative transcriptional start site. In contrast, the p150, p110, p90 and p80 isoforms are produced by proteolytic processing of the full length protein (p200). CR = cut repeat; HD = homeodomain.


The human full length CUX1 protein (p200) consists of 1505 amino acids and contains four DNA binding domains: three CUT-repeats and one CUT-homeodomain (Harada et al., 1994).
Several shortened CUX1 isoforms have been described that are named according to their molecular weight. CUX1 p75 is the product of a shortened mRNA that is generated by the use of an alternative transcription start site in exon 20 (Rong Zeng et al., 2000; Goulet et al., 2002). CUX1 p150, p110, p90 and p80 are generated by proteolytic processing of the full length protein by a nuclear isoform of Cathepsin L and other not yet identified proteases such as caspases (Goulet et al., 2004; Goulet et al., 2006; Maitra et al., 2006; Truscott et al., 2007).
The presence of DNA binding domains in the CUX1 isoforms determines their interaction with DNA and their transcriptional activity. The full length protein p200 shows unstable DNA binding, carries the CCAAT-displacement activity and functions predominantly as a transcriptional repressor. In contrast, the p110, p90, p80 and p75 isoforms show stable DNA binding and function both as transcriptional repressors or activators (Truscott et al., 2004; Goulet et al., 2002; Goulet et al., 2006; Moon et al., 2001). According to Maitra et al., the p150 isoform is incapable of DNA binding (Maitra et al., 2006).
Several posttranslational modifications are known to modulate the DNA binding activities of the CUX1 proteins. Protein kinase C and Casein kinase II are able to phosphorylate serine or threonine residues within the cut repeats (Coqueret et al., 1998b; Li et al., 2007). Protein kinase A and cyclin A/Cdk1 phosphorylate specific serine residues in a region between the Cut repeat 3 and the homeodomain (Michl et al., 2006; Santaguida et al., 2001). PCAF acetyl-transferase is able to acetylate CUX1 on a lysine residue in the homeodomain (Li et al., 2000). Both, phosphorylation and acetylation have been shown to inhibit CUX1 DNA binding (Sansregret et al., 2010; Li et al., 2000). Consistent with this, dephosphorylation by Cdc 25A phosphatase is able to increase DNA binding of CUX1 (Coqueret et al, 1998a).


Early studies suggested that in mammalian cells, CUX1 represses genes that are upregulated in differentiated tissues. Furthermore, the expression of CUX1 might be restricted to proliferating and undifferentiated cells and is inversely related to the degree of differentiation (vanden Heuvel et al., 1996; Pattison et al., 1997; van Gurp et al., 1999). More recently however, studies in mice revealed that CUX1 is also expressed in terminally differentiated cells of many tissues (Khanna-Gupta et al., 2001; Ellis et al., 2001).
Increased CUX1 expression was found in various tumour types including multiple myelomas, acute lymphoblastic leukaemia, breast carcinoma and pancreatic cancer (De Vos et al., 2002; Tsutsumi et al., 2003; Michl et al., 2005; Ripka et al., 2007).
It has been shown that the cellular expression of CUX1 mRNA and protein is elevated following TGF-beta stimulation in many cell types including fibroblasts, pancreatic cancer cells, breast cancer cells and malignant plasma cells (Fragiadaki et al., 2011; Michl et al., 2005; De Vos et al., 2002). This regulation of CUX1 expression by TGF-beta is probably mediated by p38MAPK and Smad4 signalling (Michl et al., 2005).


Studies indicate that phosphorylated CUX1 is preferentially localized in the cytoplasm whereas dephosphorylation leads to translocation into the nucleus (Sansregret et al., 2010).


The vast majority of studies describes CUX1 as a transcriptional repressor (Lievens et al., 1995; Ai et al., 1999; Catt et al., 1999a; Catt et al., 1999b; Ueda et al., 2007). The repressor activity can be mediated by competition for DNA binding sites with transcriptional activators (Kim et al., 1997; Stünkel et al., 2000), by recruitment of histone deacetylases (Li et al., 1999) or by recruitment of histone lysine methyltransferases (Nishio and Walsh, 2004). CUX1 may also negatively regulate gene expression by binding to matrix attachment regions and by modulating their association with the nuclear scaffold (Banan et al., 1997; Stünkel et al., 2000; Goebel et al., 2002; Kaul-Ghanekar et al., 2004). In contrast, the mechanisms underlying its effects on transcriptional activation are less well understood.
CUX1 is involved in at least three cellular processes important for cancer progression: cell proliferation, cell motility/invasiveness and apoptosis.

Studies indicate that the pro-proliferative effects of CUX1 are mainly mediated by the p110 isoform. This isoform is produced by proteolytic cleavage of the full length protein occuring during G1/S-transition in the cell cycle (Goulet et al., 2004; Moon et al., 2001). Cells stably transfected with p110 CUX1 showed increased proliferation due to a shortened G1-phase whereas embryonic fibroblasts obtained from CUX1 knockout mice showed elongated G1-phase and less proliferation compared to cells isolated from wild-type mice (Sansregret et al., 2006).
A genome-wide location array for p110 CUX1 binding sites in transformed and non-transformed cell lines identified numerous CUX1 target genes that are related to proliferation and cell cycle progression (Harada et al., 2008). Most of these genes are activated by p110 CUX1 including DNA polymerase-alpha, cyclin A2 and cyclin E2. In contrast, other genes are repressed such as the CDK-inhibitor p21 (Truscott et al., 2003; Nishio and Walsh, 2004; Harada et al., 2008).

Cell motility
First evidence that CUX1 plays a role in cell motility originates from knockdown studies in fibroblasts and a panel of human cancer cell lines that revealed that depletion of CUX1 leads to decreased cell migration and invasion (Michl et al., 2005). In agreement with this, cells stably expressing p110 and p75 CUX1 show increased cell migration and invasion (Kedinger et al., 2009; Cadieux et al., 2009). Additionally, tail vein injection of cells stably expressing shRNA against CUX1 resulted in reduced formation of lung metastases, whereas injection of cells stably overexpressing CUX1 led to increased lung metastases (Michl et al., 2005; Cadieux et al., 2009).
The molecular basis for these effects on cell motility was in part elucidated in a genome-wide location analysis in several cell lines (Kedinger et al., 2009). In this study, CUX1 was found to inhibit the expression of genes that repress cell migration (e.g. E-cadherin, occludin) and to turn on the expression of genes that promote cell migration (e.g. FAK, N-cadherin, vimentin) (Kedinger et al., 2009). The regulation of these genes seems to be mediated both directly by binding of CUX1 to the gene promoters but also indirectly by modulation of transcription factors and signaling proteins involved in EMT (e.g. SNAI1, SNAI2, Src, Wnt5a) (Kedinger et al., 2009; Aleksic et al., 2007; Ripka et al., 2007). Additionally, several of the CUX1 target genes are known GTPases important for actin-cytoskeleton polymerization (Kedinger et al., 2009).

Studies in pancreatic cancer cell lines showed that depletion of CUX1 by siRNA increases TNFalpha- and TRAIL-induced apoptosis whereas overexpression of CUX1 rescues from apoptosis. Additionally, treatment of xenograft tumours with siRNA for CUX1 lead to retarded tumour growth and increased apoptosis. These effects are at least in part explained by a positive regulation of the antiapoptotic protein BCL2 by CUX1 (Ripka et al., 2010a). Subsequently, the glutamate receptor GRIA3 was identified as another downstream target of CUX1 able to mediate its antiapoptotic effects (Ripka et al., 2010b).


Cut homeodomain proteins are highly conserved in evolution of metazoans. Homologues of the Drosophila melanogaster Cut protein have been described at least in human, dog and mouse (Neufeld et al., 1992; Andres et al., 1992; Valarché et al., 1993). In humans, a homologue gene, called CUX2, was described (Jacobsen et al., 2001).



A missense mutation affecting the homeodomain has been described in one patient suffering from acute myeloid leukaemia, the significance of which remains to be elucidated (Thoennissen et al., 2011).

Implicated in

Entity name
Pancreatic cancer
In pancreatic cancer CUX1 expression is elevated compared to normal pancreas tissue (Ripka et al., 2010a). Furthermore, an increased expression in high-grade tumours compared to low grade tumours was described (Michl et al., 2005).
The expression of CUX1 is accompanied by the overexpression of its downstream targets WNT5a and GRIA3 that, at least in part, mediate the proinvasive and proproliferative effects of CUX1 (Ripka et al., 2006; Ripka et al., 2010b).
Antiapoptotic effects of CUX1 in pancreatic cancer, that have been shown in in vitro studies and in xenograft models, are associated with a positive regulation of BCL2 and downregulation of tumour necrosis factor alpha and are, at least in part, mediated by the glutamate receptor GRIA3 (Ripka et al., 2010a; Ripka et al., 2010b).
Entity name
Breast cancer
In mammary carcinoma the CUX1 expression is increased in high-grade tumours compared to low grade tumours and a reverse correlation between CUX1 mRNA levels and the relapse free- and overall-survival was shown (Michl et al., 2005). Furthermore, is has been shown that the expression levels of the intron 20-initiated mRNA, that leads to the synthesis of the p75 CUX1 isoform, is specifically expressed in breast cancer and positively correlated with a diffuse infiltrative growth pattern (Goulet et al., 2002). Transgenic mice expressing p75 and p110 CUX1 under the control of the mouse mammary tumour virus-long terminal repeat developed breast cancer after a long latency period. This tumour development was accompanied by an increased activity of WNT-β-catenin signalling (Cadieux et al., 2009).


Pubmed IDLast YearTitleAuthors
101963181999CCAAT displacement protein binds to and negatively regulates human papillomavirus type 6 E6, E7, and E1 promoters.Ai W et al
173698462007CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation.Aleksic T et al
13630851992Clox, a mammalian homeobox gene related to Drosophila cut, encodes DNA-binding regulatory proteins differentially expressed during development.Andres V et al
92184881997Interaction of the nuclear matrix-associated region (MAR)-binding proteins, SATB1 and CDP/Cux, with a MAR element (L2a) in an upstream regulatory region of the mouse CD8a gene.Banan M et al
197380702009Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types.Cadieux C et al
105562021999Overexpression of CCAAT displacement protein represses the promiscuously active proximal gp91(phox) promoter.Catt D et al
106439641999DNA-binding properties of CCAAT displacement protein cut repeats.Catt D et al
94465571998DNA binding by cut homeodomain proteins is down-modulated by casein kinase II.Coqueret O et al
123604122002Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays.De Vos J et al
115441872001The transcriptional repressor CDP (Cutl1) is essential for epithelial cell differentiation of the lung and the hair follicle.Ellis T et al
214710052011High doses of TGF-β potently suppress type I collagen via the transcription factor CUX1.Fragiadaki M et al
121937172002High frequency of matrix attachment regions and cut-like protein x/CCAAT-displacement protein and B cell regulator of IgH transcription binding sites flanking Ig V region genes.Goebel P et al
150995202004A 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 et al
169727982006A novel proteolytically processed CDP/Cux isoform of 90 kDa is generated by cathepsin L.Goulet B et al
124382592002Characterization of a tissue-specific CDP/Cux isoform, p75, activated in breast tumor cells.Goulet B et al
79049991994Conserved cut repeats in the human cut homeodomain protein function as DNA binding domains.Harada R et al
180036582008Genome-wide location analysis and expression studies reveal a role for p110 CUX1 in the activation of DNA replication genes.Harada R et al
113534532001CUX2, a potential regulator of NCAM expression: genomic characterization and analysis as a positional candidate susceptibility gene for bipolar disorder.Jacobsen NJ et al
153715502004SMAR1 and Cux/CDP modulate chromatin and act as negative regulators of the TCRbeta enhancer (Ebeta).Kaul-Ghanekar R et al
196357982009p110 CUX1 homeodomain protein stimulates cell migration and invasion in part through a regulatory cascade culminating in the repression of E-cadherin and occludin.Kedinger V et al
114387452001C/EBP epsilon mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDP/cut).Khanna-Gupta A et al
94194211997Positive and negative regulation of the human thymidine kinase promoter mediated by CCAAT binding transcription factors NF-Y/CBF, dbpA, and CDP/cut.Kim EC et al
176820592007Protein kinase C-mediated modulation of FIH-1 expression by the homeodomain protein CDP/Cut/Cux.Li J et al
108529582000Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP.Li S et al
100756721999Transcriptional repression of the cystic fibrosis transmembrane conductance regulator gene, mediated by CCAAT displacement protein/cut homolog, is associated with histone deacetylation.Li S et al
93323511997CASP, a novel, highly conserved alternative-splicing product of the CDP/cut/cux gene, lacks cut-repeat and homeo DNA-binding domains, and interacts with full-length CDP in vitro.Lievens PM et al
170154742006Differentiation-induced cleavage of Cutl1/CDP generates a novel dominant-negative isoform that regulates mammary gene expression.Maitra U et al
163575362006CUTL1: a key mediator of TGFbeta-induced tumor invasion.Michl P et al
159509022005CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness.Michl P et al
115096742001S phase-specific proteolytic cleavage is required to activate stable DNA binding by the CDP/Cut homeodomain protein.Moon NS et al
13019991992Human CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut.Neufeld EJ et al
152693442004CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription.Nishio H et al
105901292000The differentiation-specific factor CDP/Cut represses transcription and replication of human papillomaviruses through a conserved silencing element.O'Connor MJ et al
90323331997CCAAT displacement protein, a regulator of differentiation-specific gene expression, binds a negative regulatory element within the 5' end of the human papillomavirus type 6 long control region.Pattison S et al
172277812007WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer.Ripka S et al
204422022010CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer.Ripka S et al
206897602010Glutamate receptor GRIA3--target of CUX1 and mediator of tumor progression in pancreatic cancer.Ripka S et al
106079012000Exon/intron structure and alternative transcripts of the CUTL1 gene.Rong Zeng W et al
207292122010Hyperphosphorylation by cyclin B/CDK1 in mitosis resets CUX1 DNA binding clock at each cell cycle.Sansregret L et al
115840182001Phosphorylation of the CCAAT displacement protein (CDP)/Cux transcription factor by cyclin A-Cdk1 modulates its DNA binding activity in G(2).Santaguida M et al
84680661993Regional localization of the CCAAT displacement protein gene (CUTL1) to 7q22 by analysis of somatic cell hybrids.Scherer SW et al
106842632000Nuclear matrix attachment regions of human papillomavirus type 16 repress or activate the E6 promoter, depending on the physical state of the viral DNA.Stünkel W et al
216745792011Novel CUX1 missense mutation in association with 7q- at leukemic transformation of MPN.Thoennissen NH et al
176819532007Carboxyl-terminal proteolytic processing of CUX1 by a caspase enables transcriptional activation in proliferating cells.Truscott M et al
129418102003Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements.Tsutsumi S et al
174967842007CCAAT displacement protein regulates nuclear factor-kappa beta-mediated chemokine transcription in melanoma cells.Ueda Y et al
79105521993The mouse homeodomain protein Phox2 regulates Ncam promoter activity in concert with Cux/CDP and is a putative determinant of neurotransmitter phenotype.Valarché I et al
88402731996Expression of a cut-related homeobox gene in developing and polycystic mouse kidney.Vanden Heuvel GB et al
106062451999The CCAAT displacement protein/cut homeodomain protein represses osteocalcin gene transcription and forms complexes with the retinoblastoma protein-related protein p107 and cyclin A.van Gurp MF et al

Other Information

Locus ID:

NCBI: 1523
MIM: 116896
HGNC: 2557
Ensembl: ENSG00000257923


dbSNP: 1523
ClinVar: 1523
TCGA: ENSG00000257923


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR1 in diseaseREACTOMER-HSA-5655302
FGFR1 mutant receptor activationREACTOMER-HSA-1839124
Signaling by cytosolic FGFR1 fusion mutantsREACTOMER-HSA-1839117
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
Intra-Golgi and retrograde Golgi-to-ER trafficREACTOMER-HSA-6811442
Intra-Golgi trafficREACTOMER-HSA-6811438

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
208426322010Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development.103
152693442004CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription.71
251244942014Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.71
172277812007WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer.68
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
159509022005CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness.60
124298222002CASP, the alternatively spliced product of the gene encoding the CCAAT-displacement protein transcription factor, is a Golgi membrane protein related to giantin.45
232125192013CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.44
243169792014Inactivating CUX1 mutations promote tumorigenesis.40
204422022010CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer.31


Benjamin Kühnemuth ; Patrick Michl

CUX1 (cut-like homeobox 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-10-01

Online version: