Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Mol. Cell. Biol. 20 (22): 8623-8633

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, November 2000, p. 8623-8633, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cell Signaling Switches HOX-PBX Complexes from Repressors to Activators of Transcription Mediated by Histone Deacetylases and Histone Acetyltransferases

Maya Saleh,1,2 Isabel Rambaldi,1 Xiang-Jiao Yang,3 and Mark S. Featherstone1,2,4,*

McGill Cancer Centre,1 Department of Biochemistry,2 Molecular Oncology Group, Department of Medicine,3 and Department of Oncology,4 McGill University, Montréal, Québec, Canada H3G 1Y6

Received 26 June 2000/Returned for modification 19 July 2000/Accepted 18 August 2000

The Hoxb1 autoregulatory element comprises three HOX-PBX binding sites. Despite the presence of HOXB1 and PBX1, this enhancer fails to activate reporter gene expression in retinoic acid-treated P19 cell monolayers. Activation requires cell aggregation in addition to RA. This suggests that HOX-PBX complexes may repress transcription under some conditions. Consistent with this, multimerized HOX-PBX binding sites repress reporter gene expression in HEK293 cells. We provide a mechanistic basis for repressor function by demonstrating that a corepressor complex, including histone deacetylases (HDACs) 1 and 3, mSIN3B, and N-CoR/SMRT, interacts with PBX1A. We map a site of interaction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex. Treatment with the deacetylase inhibitor trichostatin A not only relieves repression but also converts the HOX-PBX complex to a net activator of transcription. We show that this activation function is mediated by the recruitment of the coactivator CREB-binding protein by the HOX partner. Interestingly, HOX-PBX complexes are switched from transcriptional repressors to activators in response to protein kinase A signaling or cell aggregation. Together, our results suggest a model whereby the HOX-PBX complex can act as a repressor or activator of transcription via association with corepressors and coactivators. The model implies that cell signaling is a direct determinant of HOX-PBX function in the patterning of the animal embryo.

* Corresponding author. Mailing address: McGill Cancer Centre, McGill University, McIntyre Medical Sciences Bldg., Rm. 714, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-8937. Fax: (514) 398-6769. E-mail: mfeather{at}med.mcgill.ca.

Molecular and Cellular Biology, November 2000, p. 8623-8633, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Pbx and Prdm1a transcription factors differentially regulate subsets of the fast skeletal muscle program in zebrafish.
Z. Yao, G. H. Farr, III, S. J. Tapscott, and L. Maves (2013)
Biology Open
   Abstract »    Full Text »    PDF »
Identification and characterization of Hoxa9 binding sites in hematopoietic cells.
Y. Huang, K. Sitwala, J. Bronstein, D. Sanders, M. Dandekar, C. Collins, G. Robertson, J. MacDonald, T. Cezard, M. Bilenky, et al. (2012)
Blood 119, 388-398
   Abstract »    Full Text »    PDF »
FGFR3 is a target of the homeobox transcription factor SHOX in limb development.
E. Decker, C. Durand, S. Bender, C. Rodelsperger, A. Glaser, J. Hecht, K. U. Schneider, and G. Rappold (2011)
Hum. Mol. Genet. 20, 1524-1535
   Abstract »    Full Text »    PDF »
A Novel Gli3 Enhancer Controls the Gli3 Spatiotemporal Expression Pattern through a TALE Homeodomain Protein Binding Site.
S. Coy, J. H. Caamano, J. Carvajal, M. L. Cleary, and A.-G. Borycki (2011)
Mol. Cell. Biol. 31, 1432-1443
   Abstract »    Full Text »    PDF »
Transient Activation of Meox1 Is an Early Component of the Gene Regulatory Network Downstream of Hoxa2.
P. Kirilenko, G. He, B. S. Mankoo, M. Mallo, R. Jones, and N. Bobola (2011)
Mol. Cell. Biol. 31, 1301-1308
   Abstract »    Full Text »    PDF »
Cdx1 refines positional identity of the vertebrate hindbrain by directly repressing Mafb expression.
K. Sturgeon, T. Kaneko, M. Biemann, A. Gauthier, K. Chawengsaksophak, and S. P. Cordes (2011)
Development 138, 65-74
   Abstract »    Full Text »    PDF »
Pbx1 Represses Osteoblastogenesis by Blocking Hoxa10-Mediated Recruitment of Chromatin Remodeling Factors.
J. A. R. Gordon, M. Q. Hassan, S. Saini, M. Montecino, A. J. van Wijnen, G. S. Stein, J. L. Stein, and J. B. Lian (2010)
Mol. Cell. Biol. 30, 3531-3541
   Abstract »    Full Text »    PDF »
Transcriptional Activation by MEIS1A in Response to Protein Kinase A Signaling Requires the Transducers of Regulated CREB Family of CREB Co-activators.
S.-L. Goh, Y. Looi, H. Shen, J. Fang, C. Bodner, M. Houle, A. C.-H. Ng, R. A. Screaton, and M. Featherstone (2009)
J. Biol. Chem. 284, 18904-18912
   Abstract »    Full Text »    PDF »
Silencing Mediator for Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Attenuate Transcriptional Activation by the {beta}-Catenin-TCF4 Complex.
L.-N. Song and E. P. Gelmann (2008)
J. Biol. Chem. 283, 25988-25999
   Abstract »    Full Text »    PDF »
Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism.
P. A. Gongal and A. J. Waskiewicz (2008)
Hum. Mol. Genet. 17, 525-538
   Abstract »    Full Text »    PDF »
In Vivo Analysis of Developmentally and Evolutionarily Dynamic Protein-DNA Interactions Regulating Transcription of the Pgk2 Gene during Mammalian Spermatogenesis.
H. Yoshioka, C. B. Geyer, J. L. Hornecker, K. T. Patel, and J. R. McCarrey (2007)
Mol. Cell. Biol. 27, 7871-7885
   Abstract »    Full Text »    PDF »
Identification of a HoxA10 Activation Domain Necessary for Transcription of the Gene Encoding beta3 Integrin during Myeloid Differentiation.
L. Bei, Y. Lu, S. L. Bellis, W. Zhou, E. Horvath, and E. A. Eklund (2007)
J. Biol. Chem. 282, 16846-16859
   Abstract »    Full Text »    PDF »
HOXA10 Controls Osteoblastogenesis by Directly Activating Bone Regulatory and Phenotypic Genes.
M. Q. Hassan, R. Tare, S. H. Lee, M. Mandeville, B. Weiner, M. Montecino, A. J. van Wijnen, J. L. Stein, G. S. Stein, and J. B. Lian (2007)
Mol. Cell. Biol. 27, 3337-3352
   Abstract »    Full Text »    PDF »
Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay.
T. Rauch, Z. Wang, X. Zhang, X. Zhong, X. Wu, S. K. Lau, K. H. Kernstine, A. D. Riggs, and G. P. Pfeifer (2007)
PNAS 104, 5527-5532
   Abstract »    Full Text »    PDF »
Regulation of EphA8 Gene Expression by TALE Homeobox Transcription Factors during Development of the Mesencephalon.
S. Shim, Y. Kim, J. Shin, J. Kim, and S. Park (2007)
Mol. Cell. Biol. 27, 1614-1630
   Abstract »    Full Text »    PDF »
Functional interaction between the homeoprotein CDX1 and the transcriptional machinery containing the TATA-binding protein.
A. Calon, I. Gross, I. Davidson, M. Kedinger, I. Duluc, C. Domon-Dell, and J.-N. Freund (2007)
Nucleic Acids Res. 35, 175-185
   Abstract »    Full Text »    PDF »
Cdx-Hox code controls competence for responding to Fgfs and retinoic acid in zebrafish neural tissue.
T. Shimizu, Y.-K. Bae, and M. Hibi (2006)
Development 133, 4709-4719
   Abstract »    Full Text »    PDF »
Yin Yang 1 Physically Interacts with Hoxa11 and Represses Hoxa11-dependent Transcription.
M. P.-s. Luke, G. Sui, H. Liu, and Y. Shi (2006)
J. Biol. Chem. 281, 33226-33232
   Abstract »    Full Text »    PDF »
Evidence That the Satin Hair Mutant Gene Foxq1 Is among Multiple and Functionally Diverse Regulatory Targets for Hoxc13 during Hair Follicle Differentiation.
C. S. Potter, R. L. Peterson, J. L. Barth, N. D. Pruett, D. F. Jacobs, M. J. Kern, W. S. Argraves, J. P. Sundberg, and A. Awgulewitsch (2006)
J. Biol. Chem. 281, 29245-29255
   Abstract »    Full Text »    PDF »
The Predicted G-Protein-Coupled Receptor GPR-1 Is Required for Female Sexual Development in the Multicellular Fungus Neurospora crassa.
S. Krystofova and K. A. Borkovich (2006)
Eukaryot. Cell 5, 1503-1516
   Abstract »    Full Text »    PDF »
Persistent Transactivation by Meis1 Replaces Hox Function in Myeloid Leukemogenesis Models: Evidence for Co-Occupancy of Meis1-Pbx and Hox-Pbx Complexes on Promoters of Leukemia-Associated Genes.
G. G. Wang, M. P. Pasillas, and M. P. Kamps (2006)
Mol. Cell. Biol. 26, 3902-3916
   Abstract »    Full Text »    PDF »
Physical and Genetic Interactions Link Hox Function with Diverse Transcription Factors and Cell Signaling Proteins.
S. E. Bondos, X.-X. Tan, and K. S. Matthews (2006)
Mol. Cell. Proteomics 5, 824-834
   Abstract »    Full Text »    PDF »
Nuclear import of the transcription factor SHOOT MERISTEMLESS depends on heterodimerization with BLH proteins expressed in discrete sub-domains of the shoot apical meristem of Arabidopsis thaliana.
M. Cole, C. Nolte, and W. Werr (2006)
Nucleic Acids Res. 34, 1281-1292
   Abstract »    Full Text »    PDF »
Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax.
E. Tour, C. T. Hittinger, and W. McGinnis (2005)
Development 132, 5271-5281
   Abstract »    Full Text »    PDF »
A genomic approach to the identification and characterization of HOXA13 functional binding elements.
C. D. McCabe and J. W. Innis (2005)
Nucleic Acids Res. 33, 6782-6794
   Abstract »    Full Text »    PDF »
MyoD Targets Chromatin Remodeling Complexes to the Myogenin Locus Prior to Forming a Stable DNA-Bound Complex.
I. L. de la Serna, Y. Ohkawa, C. A. Berkes, D. A. Bergstrom, C. S. Dacwag, S. J. Tapscott, and A. N. Imbalzano (2005)
Mol. Cell. Biol. 25, 3997-4009
   Abstract »    Full Text »    PDF »
HOXA9 Activates Transcription of the Gene Encoding gp91Phox during Myeloid Differentiation.
L. Bei, Y. Lu, and E. A. Eklund (2005)
J. Biol. Chem. 280, 12359-12370
   Abstract »    Full Text »    PDF »
MEIS C Termini Harbor Transcriptional Activation Domains That Respond to Cell Signaling.
H. Huang, M. Rastegar, C. Bodner, S.-L. Goh, I. Rambaldi, and M. Featherstone (2005)
J. Biol. Chem. 280, 10119-10127
   Abstract »    Full Text »    PDF »
The roles of two C. elegans HOX co-factor orthologs in cell migration and vulva development.
L. Yang, M. Sym, and C. Kenyon (2005)
Development 132, 1413-1428
   Abstract »    Full Text »    PDF »
Transcriptional Regulation of Renin: An Update.
L. Pan and K. W. Gross (2005)
Hypertension 45, 3-8
   Abstract »    Full Text »    PDF »
Molecular interactions involved in HOXB4-induced activation of HSC self-renewal.
N. Beslu, J. Krosl, M. Laurin, N. Mayotte, K. R. Humphries, and G. Sauvageau (2004)
Blood 104, 2307-2314
   Abstract »    Full Text »    PDF »
A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation.
S. Ogawa, J. Lozach, K. Jepsen, D. Sawka-Verhelle, V. Perissi, R. Sasik, D. W. Rose, R. S. Johnson, M. G. Rosenfeld, and C. K. Glass (2004)
PNAS 101, 14461-14466
   Abstract »    Full Text »    PDF »
The HoxC4 Homeodomain Protein Mediates Activation of the Immunoglobulin Heavy Chain 3' hs1,2 Enhancer in Human B Cells: RELEVANCE TO CLASS SWITCH DNA RECOMBINATION.
E. C. Kim, C. R. Edmonston, X. Wu, A. Schaffer, and P. Casali (2004)
J. Biol. Chem. 279, 42258-42269
   Abstract »    Full Text »    PDF »
HOXB6 Protein Is Bound to CREB-binding Protein and Represses Globin Expression in a DNA Binding-dependent, PBX Interaction-independent Process.
W. Shen, D. Chrobak, K. Krishnan, H. J. Lawrence, and C. Largman (2004)
J. Biol. Chem. 279, 39895-39904
   Abstract »    Full Text »    PDF »
Integration of anteroposterior and dorsoventral regulation of Phox2b transcription in cranial motoneuron progenitors by homeodomain proteins.
O. A. Samad, M. J. Geisen, G. Caronia, I. Varlet, V. Zappavigna, J. Ericson, C. Goridis, and F. M. Rijli (2004)
Development 131, 4071-4083
   Abstract »    Full Text »    PDF »
Human Histone Deacetylase SIRT2 Interacts with the Homeobox Transcription Factor HOXA10.
N. S. Bae, M. J. Swanson, A. Vassilev, and B. H. Howard (2004)
J. Biochem. 135, 695-700
   Abstract »    Full Text »    PDF »
Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells.
A. C. M. Brun, J. M. Bjornsson, M. Magnusson, N. Larsson, P. Leveen, M. Ehinger, E. Nilsson, and S. Karlsson (2004)
Blood 103, 4126-4133
   Abstract »    Full Text »    PDF »
Differential and Common Leukemogenic Potentials of Multiple NUP98-Hox Fusion Proteins Alone or with Meis1.
N. Pineault, C. Abramovich, H. Ohta, and R. K. Humphries (2004)
Mol. Cell. Biol. 24, 1907-1917
   Abstract »    Full Text »    PDF »
HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2.
Y. Lu, I. Goldenberg, L. Bei, J. Andrejic, and E. A. Eklund (2003)
J. Biol. Chem. 278, 47792-47802
   Abstract »    Full Text »    PDF »
Interacting Transcription Factors from the Three-Amino Acid Loop Extension Superclass Regulate Tuber Formation.
H. Chen, F. M. Rosin, S. Prat, and D. J. Hannapel (2003)
Plant Physiology 132, 1391-1404
   Abstract »    Full Text »    PDF »
Specific homeodomain-DNA interactions are required for HOX11-mediated transformation.
B. M. Owens, Y.-X. Zhu, T.-C. Suen, P.-X. Wang, J. F. Greenblatt, P. E. Goss, and R. G. Hawley (2003)
Blood 101, 4966-4974
   Abstract »    Full Text »    PDF »
Selective Inhibition of Class Switching to IgG and IgE by Recruitment of the HoxC4 and Oct-1 Homeodomain Proteins and Ku70/Ku86 to Newly Identified ATTT cis-Elements.
A. Schaffer, E. C. Kim, X. Wu, H. Zan, L. Testoni, S. Salamon, A. Cerutti, and P. Casali (2003)
J. Biol. Chem. 278, 23141-23150
   Abstract »    Full Text »    PDF »
Reduced Proliferative Capacity of Hematopoietic Stem Cells Deficient in Hoxb3 and Hoxb4.
J. M. Bjornsson, N. Larsson, A. C. M. Brun, M. Magnusson, E. Andersson, P. Lundstrom, J. Larsson, E. Repetowska, M. Ehinger, R. K. Humphries, et al. (2003)
Mol. Cell. Biol. 23, 3872-3883
   Abstract »    Full Text »    PDF »
Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1.
N. Pineault, C. Buske, M. Feuring-Buske, C. Abramovich, P. Rosten, D. E. Hogge, P. D. Aplan, and R. K. Humphries (2003)
Blood 101, 4529-4538
   Abstract »    Full Text »    PDF »
Overexpression of a Knotted-Like Homeobox Gene of Potato Alters Vegetative Development by Decreasing Gibberellin Accumulation.
F. M. Rosin, J. K. Hart, H. T. Horner, P. J. Davies, and D. J. Hannapel (2003)
Plant Physiology 132, 106-117
   Abstract »    Full Text »    PDF »
Gene Expression Profiling Reveals Progesterone-Mediated Cell Cycle and Immunoregulatory Roles of Hoxa-10 in the Preimplantation Uterus.
M. W. M. Yao, H. Lim, D. J. Schust, S. E. Choe, A. Farago, Y. Ding, S. Michaud, G. M. Church, and R. L. Maas (2003)
Mol. Endocrinol. 17, 610-627
   Abstract »    Full Text »    PDF »
Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signaling subdivides the HoxB genes in two distinct groups.
S. Bel-Vialar, N. Itasaki, and R. Krumlauf (2003)
Development 129, 5103-5115
   Abstract »    Full Text »    PDF »
Requirements for transcriptional repression and activation by Engrailed in Drosophila embryos.
C. Alexandre and J.-P. Vincent (2003)
Development 130, 729-739
   Abstract »    Full Text »    PDF »
Transcriptional Repression of Peri-Implantation EMX2 Expression in Mammalian Reproduction by HOXA10.
P. J. Troy, G. S. Daftary, C. N. Bagot, and H. S. Taylor (2003)
Mol. Cell. Biol. 23, 1-13
   Abstract »    Full Text »    PDF »
Human MI-ER1 Alpha and Beta Function as Transcriptional Repressors by Recruitment of Histone Deacetylase 1 to Their Conserved ELM2 Domain.
Z. Ding, L. L. Gillespie, and G. D. Paterno (2003)
Mol. Cell. Biol. 23, 250-258
   Abstract »    Full Text »    PDF »
Direct Interactions between Corepressors and Coactivators Permit the Integration of Nuclear Receptor-Mediated Repression and Activation.
X. Li, E. A. Kimbrel, D. J. Kenan, and D. P. MCDonnell (2002)
Mol. Endocrinol. 16, 1482-1491
   Abstract »    Full Text »    PDF »
Changing homeodomain residues 2 and 3 of Hoxa1 alters its activity in a cell-type and enhancer dependent manner.
S. Remacle, C. Shaw-Jackson, C. Matis, X. Lampe, J. Picard, and R. Rezsohazy (2002)
Nucleic Acids Res. 30, 2663-2668
   Abstract »    Full Text »    PDF »
The Transcription Factor B-Myb Is Maintained in an Inhibited State in Target Cells through Its Interaction with the Nuclear Corepressors N-CoR and SMRT.
X. Li and D. P. McDonnell (2002)
Mol. Cell. Biol. 22, 3663-3673
   Abstract »    Full Text »    PDF »
Xpbx1b and Xmeis1b play a collaborative role in hindbrain and neural crest gene expression in Xenopus embryos.
R. Maeda, A. Ishimura, K. Mood, E. K. Park, A. M. Buchberg, and I. O. Daar (2002)
PNAS 99, 5448-5453
   Abstract »    Full Text »    PDF »
p65-NF{kappa}B synergizes with Notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR.
L. Espinosa, S. Santos, J. Ingles-Esteve, P. Munoz-Canoves, and A. Bigas (2002)
J. Cell Sci. 115, 1295-1303
   Abstract »    Full Text »    PDF »
Meis family proteins are required for hindbrain development in the zebrafish.
S.-K. Choe, N. Vlachakis, and C. G. Sagerstrom (2002)
Development 129, 585-595
   Abstract »    Full Text »    PDF »
Identification of Genes That Mediate Sensitivity to Cisplatin.
H. Niedner, R. Christen, X. Lin, A. Kondo, and S. B. Howell (2001)
Mol. Pharmacol. 60, 1153-1160
   Abstract »    Full Text »    PDF »
Proliferation of primitive myeloid progenitors can be reversibly induced by HOXA10.
J. M. Bjornsson, E. Andersson, P. Lundstrom, N. Larsson, X. Xu, E. Repetowska, R. K. Humphries, and S. Karlsson (2001)
Blood 98, 3301-3308
   Abstract »    Full Text »    PDF »
Critical Roles of a Cyclic AMP Responsive Element and an E-box in Regulation of Mouse Renin Gene Expression.
L. Pan, T. A. Black, Q. Shi, C. A. Jones, N. Petrovic, J. Loudon, C. Kane, C. D. Sigmund, and K. W. Gross (2001)
J. Biol. Chem. 276, 45530-45538
   Abstract »    Full Text »    PDF »
The HOX Homeodomain Proteins Block CBP Histone Acetyltransferase Activity.
W.-f. Shen, K. Krishnan, H. J. Lawrence, and C. Largman (2001)
Mol. Cell. Biol. 21, 7509-7522
   Abstract »    Full Text »    PDF »
Functional Analysis of the Conserved Domains of a Rice KNOX Homeodomain Protein, OSH15.
H. Nagasaki, T. Sakamoto, Y. Sato, and M. Matsuoka (2001)
PLANT CELL 13, 2085-2098
   Abstract »    Full Text »    PDF »
Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia.
A. Tkatchenko, R. Visconti, L Shang, T Papenbrock, N. Pruett, T Ito, M Ogawa, and A Awgulewitsch (2001)
Development 128, 1547-1558
   Abstract »    PDF »
An Abd-B Class HOX{middle dot}PBX Recognition Sequence Is Required for Expression from the Mouse Ren-1c Gene.
L. Pan, Y. Xie, T. A. Black, C. A. Jones, S. C. Pruitt, and K. W. Gross (2001)
J. Biol. Chem. 276, 32489-32494
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882