CUTL1 explained

Cux1 (CUTL1, CDP, CDP/Cux) is a homeodomain protein that in humans is encoded by the CUX1 gene.^{[1] [2] [3] [4]}

Function

The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It regulates gene expression, morphogenesis, and differentiation and it also plays a role in cell cycle progression, particularly at S-phase. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined, and the p200 isoform of Cux1 is processed proteolytically to smaller active isoforms, such as p110. Cux1 DNA binding is stimulated by activation of the PAR2/F2RL1 cell-surface G-protein-coupled receptor in fibroblasts and breast-cancer epithelial cells to regulate Matrix metalloproteinase 10, Interleukin1-alpha, and Cyclo-oxygenase 2 (COX2) genes.^[5]

Role in tumor growth

Genetic data from over 7,600 cancer patients shows that over 1% has the deactivated CUX1 which links to progression of tumor growth. Researchers from the Wellcome Trust Sanger Institute reported that the mutation of CUX1 reduces the inhibitory effects of a biological inhibitor, PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), resulted in higher activity of the growth promoting enzyme, phosphoinositide 3-kinase (PI3K) which leads to tumor progression. Although CUX1 is mutated at a lower rate compared to other known gene mutations that cause cancer, this deactivated gene is found across many cancer types in this study to be the underlying cause of the disease.^{[6] [7]}

CASP

The CUX1 gene Alternatively Spliced Product was first reported in 1997.^[8] The CUX1 gene has up to 33 exons. CASP mRNA includes exons 1 through 14 and 25 through 33.^[9] The human CASP protein is predicted to contain 678 amino acids, of which 400 are shared with CUTL1.^[8] CASP protein is approximately 80 kD.^[8] It lacks the DNA binding region of CUTL1,^{[8] [10]} but instead contains a trans-membrane domain that allows it to insert into lipid bilayers.^[10] It has been localized to the Golgi apparatus.^[10]

CASP has been reported to be part of a complex with Golgin 84 that tethers COPI vesicles and is important for retrograde transport in the Golgi and between the Golgi and endoplasmic reticulum.^[11] The targeting of vesicles involves tethers and SNAREs.^[11]

Interactions

Cux1 (CUTL1, CDP, CDP/Cux) has been shown to interact with:

• CREB binding protein,^[12]
• Retinoblastoma protein,^[13] and
• SATB1^[14]

These physical interactions are reported in BioPlex 2.0

• MAGEA10
• EXT2
• RAB30
• HLA-DQA1
• STX6
• WDR83
• SLC39A4
• LAMP1
• POTEB
• SLC39A12

Further reading

• Ottolenghi S, Mantovani R, Nicolis S, Ronchi A, Giglioni B . DNA sequences regulating human globin gene transcription in nondeletional hereditary persistence of fetal hemoglobin . Hemoglobin . 13 . 6 . 523–41 . 1990 . 2481658 . 10.3109/03630268908993104 .
• Nepveu A . Role of the multifunctional CDP/Cut/Cux homeodomain transcription factor in regulating differentiation, cell growth and development . Gene . 270 . 1–2 . 1–15 . 2001 . 11403998 . 10.1016/S0378-1119(01)00485-1 .
• Neufeld EJ, Skalnik DG, Lievens PM, Orkin SH . Human CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut . Nat. Genet. . 1 . 1 . 50–5 . 1993 . 1301999 . 10.1038/ng0492-50 . 37107643 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Chernousov MA, Stahl RC, Carey DJ . Schwann cells secrete a novel collagen-like adhesive protein that binds N-syndecan . J. Biol. Chem. . 271 . 23 . 13844–53 . 1996 . 8662884 . 10.1074/jbc.271.23.13844 . free .
• Lievens PM, Tufarelli C, Donady JJ, Stagg A, Neufeld EJ . CASP, 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 . Gene . 197 . 1–2 . 73–81 . 1997 . 9332351 . 10.1016/S0378-1119(97)00243-6 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Chattopadhyay S, Whitehurst CE, Chen J . A nuclear matrix attachment region upstream of the T cell receptor beta gene enhancer binds Cux/CDP and SATB1 and modulates enhancer-dependent reporter gene expression but not endogenous gene expression . J. Biol. Chem. . 273 . 45 . 29838–46 . 1998 . 9792700 . 10.1074/jbc.273.45.29838 . free .
• Liu J, Barnett A, Neufeld EJ, Dudley JP . Homeoproteins CDP and SATB1 Interact: Potential for Tissue-Specific Regulation . Mol. Cell. Biol. . 19 . 7 . 4918–26 . 1999 . 10373541 . 84297 . 10.1128/mcb.19.7.4918.
• Rong Zeng W, Soucie E, Sung Moon N, Martin-Soudant N, Bérubé G, Leduy L, Nepveu A . Exon/intron structure and alternative transcripts of the CUTL1 gene . Gene . 241 . 1 . 75–85 . 2000 . 10607901 . 10.1016/S0378-1119(99)00465-5 .
• Martin-Soudant N, Drachman JG, Kaushansky K, Nepveu A . CDP/Cut DNA binding activity is down-modulated in granulocytes, macrophages and erythrocytes but remains elevated in differentiating megakaryocytes . Leukemia . 14 . 5 . 863–73 . 2000 . 10803519 . 10.1038/sj.leu.2401764 . 19998783 .
• Li S, Aufiero B, Schiltz RL, Walsh MJ . Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP . Proc. Natl. Acad. Sci. U.S.A. . 97 . 13 . 7166–71 . 2000 . 10852958 . 16517 . 10.1073/pnas.130028697 . 2000PNAS...97.7166L . free .
• Nirodi C, Hart J, Dhawan P, Moon NS, Nepveu A, Richmond A . The Role of CDP in the Negative Regulation of CXCL1 Gene Expression . J. Biol. Chem. . 276 . 28 . 26122–31 . 2001 . 11371564 . 2665279 . 10.1074/jbc.M102872200 . free .
• Moon NS, Premdas P, Truscott M, Leduy L, Bérubé G, Nepveu A . S Phase-Specific Proteolytic Cleavage Is Required To Activate Stable DNA Binding by the CDP/Cut Homeodomain Protein . Mol. Cell. Biol. . 21 . 18 . 6332–45 . 2001 . 11509674 . 87367 . 10.1128/MCB.21.18.6332-6345.2001 .
• Santaguida M, Ding Q, Bérubé G, Truscott M, Whyte P, Nepveu A . Phosphorylation of the CCAAT displacement protein (CDP)/Cux transcription factor by cyclin A-Cdk1 modulates its DNA binding activity in G(2) . J. Biol. Chem. . 276 . 49 . 45780–90 . 2002 . 11584018 . 10.1074/jbc.M107978200 . free .
• Dintilhac A, Bernués J . HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences . J. Biol. Chem. . 277 . 9 . 7021–8 . 2002 . 11748221 . 10.1074/jbc.M108417200 . 39560486 . free .

Notes and References

1. Scherer SW, Neufeld EJ, Lievens PM, Orkin SH, Kim J, Tsui LC . Regional localization of the CCAAT displacement protein gene (CUTL1) to 7q22 by analysis of somatic cell hybrids . Genomics . 15 . 3 . 695–6 . May 1993 . 8468066 . 10.1006/geno.1993.1130 .
2. Glöckner G, Scherer S, Schattevoy R, Boright A, Weber J, Tsui LC, Rosenthal A . Large-Scale Sequencing of Two Regions in Human Chromosome 7q22: Analysis of 650 kb of Genomic Sequence around the EPO and CUTL1 Loci Reveals 17 Genes . Genome Res. . 8 . 10 . 1060–73 . December 1998 . 9799793 . 310788 . 10.1101/gr.8.10.1060 .
3. Oka T, Ungar D, Hughson FM, Krieger M . The COG and COPI Complexes Interact to Control the Abundance of GEARs, a Subset of Golgi Integral Membrane Proteins . Mol. Biol. Cell . 15 . 5 . 2423–35 . April 2004 . 15004235 . 404034 . 10.1091/mbc.E03-09-0699 .
4. Web site: Entrez Gene: CUTL1 cut-like 1, CCAAT displacement protein (Drosophila).
5. Wilson BJ, Harada R, LeDuy L, Hollenberg MD, Nepveu A . CUX1 transcription factor is a downstream effector of the proteinase-activated receptor 2 (PAR2) . J. Biol. Chem. . 284 . 1 . 36–45 . January 2009 . 18952606 . 10.1074/jbc.M803808200 . free .
6. Web site: Gene promotes one in a hundred of tumours. Press Release. Wellcome Trust Sanger Institute. 8 December 2013. 17 December 2013.
7. Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, Tiffen JC, Kober C, Green AR, Massie CE, Nangalia J, Lempidaki S, Döhner H, Döhner K, Bray SJ, McDermott U, Papaemmanuil E, Campbell PJ, Adams DJ . Inactivating CUX1 mutations promote tumorigenesis . Nature Genetics . 46 . 1 . 33–8 . 2013 . 24316979 . 10.1038/ng.2846 . 3 . 3874239.
8. Lievens PM, Tufarelli C, Donady JJ, Stagg A, Neufeld EJ . CASP, 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 . Gene . 197 . 1–2 . 73–81 . 1997 . 9332351 . 10.1016/s0378-1119(97)00243-6.
9. Ramdzan ZM, Nepveu A . CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers . Nature Reviews Cancer . 14 . 10 . 673–82 . 2014 . 25190083 . 10.1038/nrc3805 . 20468440 .
10. Gillingham AK, Pfeifer AC, Munro S . CASP, the alternatively spliced product of the gene encoding the CCAAT-displacement protein transcription factor, is a Golgi membrane protein related to giantin . Molecular Biology of the Cell . 13 . 11 . 3761–74 . 2002 . 12429822 . 133590 . 10.1091/mbc.E02-06-0349 .
11. Malsam J, Satoh A, Pelletier L, Warren G . Golgin tethers define subpopulations of COPI vesicles . Science . 307 . 5712 . 1095–8 . 2005 . 15718469 . 10.1126/science.1108061 . 2005Sci...307.1095M . 12601850 .
12. Li S, Aufiero B, Schiltz RL, Walsh MJ . Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP . Proc. Natl. Acad. Sci. U.S.A. . 97 . 13 . 7166–71 . June 2000 . 10852958 . 16517 . 10.1073/pnas.130028697 . 2000PNAS...97.7166L . free .
13. Gupta S, Luong MX, Bleuming SA, Miele A, Luong M, Young D, Knudsen ES, Van Wijnen AJ, Stein JL, Stein GS . Tumor suppressor pRB functions as a co-repressor of the CCAAT displacement protein (CDP/cut) to regulate cell cycle controlled histone H4 transcription . J. Cell. Physiol. . 196 . 3 . 541–56 . September 2003 . 12891711 . 10.1002/jcp.10335 . 2287673 .
14. Liu J, Barnett A, Neufeld EJ, Dudley JP . Homeoproteins CDP and SATB1 interact: potential for tissue-specific regulation . Mol. Cell. Biol. . 19 . 7 . 4918–26 . July 1999 . 10373541 . 84297 . 10.1128/mcb.19.7.4918.