Development, Vol 116, Issue 2 321-334, Copyright © 1992 by Company of Biologists

JOURNAL ARTICLES

Clox, a mammalian homeobox gene related to Drosophila cut, encodes DNA-binding regulatory proteins differentially expressed during development

V Andres, B Nadal-Ginard and V Mahdavi
Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts.

We report the isolation of a cDNA encoding a mammalian homeoprotein related to the Drosophila cut gene product, called Clox, for Cut like homeobox. In addition to the homeodomain, three 73-amino acid repeats, the so-called cut repeats, are also conserved between Cut and the mammalian counterpart described here. This conservation suggests that the cut repeat motif may define a new class of homeoproteins. Both cloned and endogenous Clox proteins are nuclear DNA-binding proteins with very similar sequence specificity. Western blot analysis revealed several distinct Clox protein species in a variety of tissues and cell types. The relative abundance of these proteins is regulated during mouse development and cell differentiation in culture. Interestingly, approximately 180-190 x 10(3) M(r) Clox proteins predominate in early embryos and are upregulated in committed myoblasts and chondrocytes, but downregulated upon terminal differentiation. Clox DNA-binding activity is correlated with the abundance of these proteins. In contrast, larger Clox protein species (approximately 230-250 x 10(3) M(r)) are detected mainly in adult tissues and in terminally differentiated cells. Cotransfection experiments show that Clox proteins can function as repressors of tissue-specific gene transcription. Thus, Clox, like their Drosophila counterparts, are candidate regulators of cell-fate specification in diverse differentiation programs.

This article has been cited by other articles:

				U. Maitra, J. Seo, M. M. Lozano, and J. P. Dudley Differentiation-Induced Cleavage of Cutl1/CDP Generates a Novel Dominant-Negative Isoform That Regulates Mammary Gene Expression Mol. Cell. Biol., October 15, 2006; 26(20): 7466 - 7478. [Abstract] [Full Text] [PDF]

				H. Belanger, P. Beaulieu, C. Moreau, D. Labuda, T. J. Hudson, and D. Sinnett Functional promoter SNPs in cell cycle checkpoint genes Hum. Mol. Genet., September 15, 2005; 14(18): 2641 - 2648. [Abstract] [Full Text] [PDF]

				A. Khanna-Gupta, T. Zibello, H. Sun, P. Gaines, and N. Berliner Chromatin immunoprecipitation (ChIP) studies indicate a role for CCAAT enhancer binding proteins alpha and epsilon (C/EBPalpha and C/EBPepsilon ) and CDP/cut in myeloid maturation-induced lactoferrin gene expression Blood, May 1, 2003; 101(9): 3460 - 3468. [Abstract] [Full Text] [PDF]

				B. Goulet, P. Watson, M. Poirier, L. Leduy, G. Berube, S. Meterissian, P. Jolicoeur, and A. Nepveu Characterization of a Tissue-specific CDP/Cux Isoform, p75, Activated in Breast Tumor Cells Cancer Res., November 15, 2002; 62(22): 6625 - 6633. [Abstract] [Full Text] [PDF]

				Q. Zhu and J. P. Dudley CDP Binding to Multiple Sites in the Mouse Mammary Tumor Virus Long Terminal Repeat Suppresses Basal and Glucocorticoid-Induced Transcription J. Virol., March 1, 2002; 76(5): 2168 - 2179. [Abstract] [Full Text] [PDF]

				M. X. Luong, C. M. van der Meijden, D. Xing, R. Hesselton, E. S. Monuki, S. N. Jones, J. B. Lian, J. L. Stein, G. S. Stein, E. J. Neufeld, et al. Genetic Ablation of the CDP/Cux Protein C Terminus Results in Hair Cycle Defects and Reduced Male Fertility Mol. Cell. Biol., March 1, 2002; 22(5): 1424 - 1437. [Abstract] [Full Text] [PDF]

				A. M. Sinclair, J. A. Lee, A. Goldstein, D. Xing, S. Liu, R. Ju, P. W. Tucker, E. J. Neufeld, and R. H. Scheuermann Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice Blood, December 15, 2001; 98(13): 3658 - 3667. [Abstract] [Full Text] [PDF]

				N. S. Moon, P. Premdas, M. Truscott, L. Leduy, G. Berube, and A. Nepveu S Phase-Specific Proteolytic Cleavage Is Required To Activate Stable DNA Binding by the CDP/Cut Homeodomain Protein Mol. Cell. Biol., September 15, 2001; 21(18): 6332 - 6345. [Abstract] [Full Text] [PDF]

				Q. Zhu, K. Gregg, M. Lozano, J. Liu, and J. P. Dudley CDP Is a Repressor of Mouse Mammary Tumor Virus Expression in the Mammary Gland J. Virol., July 15, 2000; 74(14): 6348 - 6357. [Abstract] [Full Text]

				W. Ai, J. Narahari, and A. Roman Yin Yang 1 Negatively Regulates the Differentiation-Specific E1 Promoter of Human Papillomavirus Type 6 J. Virol., June 1, 2000; 74(11): 5198 - 5205. [Abstract] [Full Text]

				A. Tavares, T Tsukui, and J. Izpisua Belmonte Evidence that members of the Cut/Cux/CDP family may be involved in AER positioning and polarizing activity during chick limb development Development, January 12, 2000; 127(23): 5133 - 5144. [Abstract] [PDF]

				D. Catt, S. Hawkins, A. Roman, W. Luo, and D. G. Skalnik Overexpression of CCAAT Displacement Protein Represses the Promiscuously Active Proximal gp91phox Promoter Blood, November 1, 1999; 94(9): 3151 - 3160. [Abstract] [Full Text] [PDF]

				B. M. Jacobsen and D. G. Skalnik YY1 Binds Five cis-Elements and Trans-activates the Myeloid Cell-restricted gp91phox Promoter J. Biol. Chem., October 15, 1999; 274(42): 29984 - 29993. [Abstract] [Full Text] [PDF]

				J. Liu, A. Barnett, E. J. Neufeld, and J. P. Dudley Homeoproteins CDP and SATB1 Interact: Potential for Tissue-Specific Regulation Mol. Cell. Biol., July 1, 1999; 19(7): 4918 - 4926. [Abstract] [Full Text] [PDF]

				K. S. Voo and D. G. Skalnik Elf-1 and PU.1 Induce Expression of gp91phox Via a Promoter Element Mutated in a Subset of Chronic Granulomatous Disease Patients Blood, May 15, 1999; 93(10): 3512 - 3520. [Abstract] [Full Text] [PDF]

				W. Ai, E. Toussaint, and A. Roman CCAAT Displacement Protein Binds to and Negatively Regulates Human Papillomavirus Type 6 E6, E7, and E1 Promoters J. Virol., May 1, 1999; 73(5): 4220 - 4229. [Abstract] [Full Text]

				S. Li, L. Moy, N. Pittman, G. Shue, B. Aufiero, E. J. Neufeld, N. S. LeLeiko, and M. J. Walsh Transcriptional Repression of the Cystic Fibrosis Transmembrane Conductance Regulator Gene, Mediated by CCAAT Displacement Protein/cut Homolog, Is Associated with Histone Deacetylation J. Biol. Chem., March 19, 1999; 274(12): 7803 - 7815. [Abstract] [Full Text] [PDF]

				Z. Wang, A. Goldstein, R.-T. Zong, D. Lin, E. J. Neufeld, R. H. Scheuermann, and P. W. Tucker Cux/CDP Homeoprotein Is a Component of NF-µNR and Represses the Immunoglobulin Heavy Chain Intronic Enhancer by Antagonizing the Bright Transcription Activator Mol. Cell. Biol., January 1, 1999; 19(1): 284 - 295. [Abstract] [Full Text] [PDF]

				V. J. Lannoy, T. R. Burglin, G. G. Rousseau, and F. P. Lemaigre Isoforms of Hepatocyte Nuclear Factor-6 Differ in DNA-binding Properties, Contain a Bifunctional Homeodomain, and Define the New ONECUT Class of Homeodomain Proteins J. Biol. Chem., May 29, 1998; 273(22): 13552 - 13562. [Abstract] [Full Text] [PDF]

				S. Suzuki, A. Kumatori, I.-A. Haagen, Y. Fujii, M. A. Sadat, H. L. Jun, Y. Tsuji, D. Roos, and M. Nakamura PU.1 as an essential activator for the expression of gp91phox gene in human peripheral neutrophils, monocytes, and B lymphocytes PNAS, May 26, 1998; 95(11): 6085 - 6090. [Abstract] [Full Text] [PDF]

				L. A. Johnston, B. D. Ostrow, C. Jasoni, and K. Blochlinger The Homeobox Gene cut Interacts Genetically With the Homeotic Genes proboscipedia and Antennapedia Genetics, May 1, 1998; 149(1): 131 - 142. [Abstract] [Full Text] [PDF]

				O. Coqueret, N. Martin, G. Berube, M. Rabbat, D. W. Litchfield, and A. Nepveu DNA Binding by Cut Homeodomain Proteins Is Down-modulated by Casein Kinase II J. Biol. Chem., January 30, 1998; 273(5): 2561 - 2566. [Abstract] [Full Text] [PDF]

				L. A. Dickinson, C. D. Dickinson, and T. Kohwi-Shigematsu An Atypical Homeodomain in SATB1 Promotes Specific Recognition of the Key Structural Element in a Matrix Attachment Region J. Biol. Chem., April 25, 1997; 272(17): 11463 - 11470. [Abstract] [Full Text] [PDF]

				O. Coqueret, G. Berube, and A. Nepveu DNA Binding by Cut Homeodomain Proteins Is Down-modulated by Protein Kinase C J. Biol. Chem., October 4, 1996; 271(40): 24862 - 24868. [Abstract] [Full Text] [PDF]

				S. E. Quaggin, G. B.V. Heuvel, K. Golden, R. Bodmer, and P. Igarashi Primary Structure, Neural-specific Expression, and Chromosomal Localization of Cux-2, a Second Murine Homeobox Gene Related to Drosophila cut J. Biol. Chem., September 13, 1996; 271(37): 22624 - 22634. [Abstract] [Full Text] [PDF]

				W. Luo and D. G. Skalnik CCAAT Displacement Protein Competes with Multiple Transcriptional Activators for Binding to Four Sites in the Proximal gp91phox Promoter J. Biol. Chem., July 26, 1996; 271(30): 18203 - 18210. [Abstract] [Full Text] [PDF]

				V. Andrés, M. Cervera, and V. Mahdavi Determination of the Consensus Binding Site for MEF2 Expressed in Muscle and Brain Reveals Tissue-specific Sequence Constraints J. Biol. Chem., October 6, 1995; 270(40): 23246 - 23249. [Abstract] [Full Text] [PDF]

				P. M. J. Lievens, J. J. Donady, C. Tufarelli, and E. J. Neufeld Repressor Activity of CCAAT Displacement Protein in HL-60 Myeloid Leukemia Cells J. Biol. Chem., May 26, 1995; 270(21): 12745 - 12750. [Abstract] [Full Text] [PDF]

				R Brewster and R Bodmer Origin and specification of type II sensory neurons in Drosophila Development, January 9, 1995; 121(9): 2923 - 2936. [Abstract] [PDF]

				V Andres, M D Chiara, and V Mahdavi A new bipartite DNA-binding domain: cooperative interaction between the cut repeat and homeo domain of the cut homeo proteins. Genes & Dev., January 15, 1994; 8(2): 245 - 257. [Abstract] [PDF]

				N. S. Moon, G. Berube, and A. Nepveu CCAAT Displacement Activity Involves CUT Repeats 1 and 2, Not the CUT Homeodomain J. Biol. Chem., September 29, 2000; 275(40): 31325 - 31334. [Abstract] [Full Text] [PDF]

				S. M. Hawkins, T. Kohwi-Shigematsu, and D. G. Skalnik The Matrix Attachment Region-binding Protein SATB1 Interacts with Multiple Elements within the gp91phox Promoter and Is Down-regulated during Myeloid Differentiation J. Biol. Chem., November 21, 2001; 276(48): 44472 - 44480. [Abstract] [Full Text] [PDF]