This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Asahara, H.
Right arrow Articles by Montminy, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Asahara, H.
Right arrow Articles by Montminy, M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 1999, p. 8219-8225, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Pbx-Hox Heterodimers Recruit Coactivator-Corepressor Complexes in an Isoform-Specific Manner

Hiroshi Asahara,1 Sanjoy Dutta,1 Hung-Ying Kao,2 Ronald M. Evans,2 and Marc Montminy3,*

Joslin Diabetes Center3 and Department of Cell Biology, Harvard Medical School,1 Boston, Massachusetts 02215, and Howard Hughes Medical Institute, Salk Institute, La Jolla, California 920372

Received 28 June 1999/Returned for modification 17 August 1999/Accepted 8 September 1999

Homeobox (hox) proteins have been shown to regulate cell fate and segment identity by promoting the expression of specific genetic programs. In contrast to their restricted biological action in vivo, however, most homeodomain factors exhibit promiscuous DNA binding properties in vitro, suggesting a requirement for additional cofactors that enhance target site selectivity. In this regard, the pbx family of homeobox genes has been found to heterodimerize with and thereby augment the DNA binding activity of certain hox proteins on a subset of potential target sites. Here we examine the transcriptional properties of a forced hox-pbx heterodimer containing the pancreas-specific orphan homeobox factor pdx fused to pbx-1a. Compared to the pdx monomer, the forced pdx-pbx1a dimer, displayed 10- to 20-fold-higher affinity for a consensus hox-pbx binding site but was completely unable to bind a hox monomer recognition site. The pdx-pbx dimer stimulated target gene expression via an N-terminal trans-activation domain in pdx that interacts with the coactivator CREB binding protein. The pdx-pbx dimer was also found to repress transcription via a C-terminal domain in pbx-1a that associates with the corepressors SMRT and NCoR. The transcriptional properties of the pdx-pbx1 complex appear to be regulated at the level of alternative splicing; a pdx-pbx polypeptide containing the pbx1b isoform, which lacks the C-terminal extension in pbx1a, was unable to repress target gene expression via NCoR-SMRT. Since pbx1a and pbx1b are differentially expressed in endocrine versus exocrine compartments of the adult pancreas, our results illustrate a novel mechanism by which pbx proteins may modulate the expression of specific genetic programs, either positively or negatively, during development.

* Corresponding author. Present address: Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 453-4100, ext. 1107. E-mail: MONTMINY{at}SALK.EDU.

Molecular and Cellular Biology, December 1999, p. 8219-8225, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Song, L.-N., Gelmann, E. P. (2008). Silencing Mediator for Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Attenuate Transcriptional Activation by the {beta}-Catenin-TCF4 Complex. J. Biol. Chem. 283: 25988-25999 [Abstract] [Full Text]  
  • Yoshioka, H., Geyer, C. B., Hornecker, J. L., Patel, K. T., McCarrey, J. R. (2007). In Vivo Analysis of Developmentally and Evolutionarily Dynamic Protein-DNA Interactions Regulating Transcription of the Pgk2 Gene during Mammalian Spermatogenesis. Mol. Cell. Biol. 27: 7871-7885 [Abstract] [Full Text]  
  • Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., Tujague, M., Strom, A., Treuter, E., Warner, M., Gustafsson, J.-A. (2007). Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol. Rev. 87: 905-931 [Abstract] [Full Text]  
  • Deramaudt, T. B., Sachdeva, M. M., Wescott, M. P., Chen, Y., Stoffers, D. A., Rustgi, A. K. (2006). The PDX1 Homeodomain Transcription Factor Negatively Regulates the Pancreatic Ductal Cell-specific Keratin 19 Promoter. J. Biol. Chem. 281: 38385-38395 [Abstract] [Full Text]  
  • Shimizu, T., Bae, Y.-K., Hibi, M. (2006). Cdx-Hox code controls competence for responding to Fgfs and retinoic acid in zebrafish neural tissue. Development 133: 4709-4719 [Abstract] [Full Text]  
  • Tanaka, H., Matsumura, I., Itoh, K., Hatsuyama, A., Shikamura, M., Satoh, Y., Heike, T., Nakahata, T., Kanakura, Y. (2006). HOX Decoy Peptide Enhances the Ex Vivo Expansion of Human Umbilical Cord Blood CD34+ Hematopoietic Stem Cells/Hematopoietic Progenitor Cells. Stem Cells 24: 2592-2602 [Abstract] [Full Text]  
  • Yu, J., Palmer, C., Alenghat, T., Li, Y., Kao, G., Lazar, M. A. (2006). The corepressor silencing mediator for retinoid and thyroid hormone receptor facilitates cellular recovery from DNA double-strand breaks.. Cancer Res. 66: 9316-9322 [Abstract] [Full Text]  
  • Volinic, J. L., Lee, J. H., Eto, K., Kaur, V., Thomas, M. K. (2006). Overexpression of the Coactivator Bridge-1 Results in Insulin Deficiency and Diabetes. Mol. Endocrinol. 20: 167-182 [Abstract] [Full Text]  
  • Tang, Q., Mazur, M., Mellon, P. L. (2005). The Protein Kinase C Pathway Acts through Multiple Transcription Factors to Repress Gonadotropin-Releasing Hormone Gene Expression in Hypothalamic GT1-7 Neuronal Cells. Mol. Endocrinol. 19: 2769-2779 [Abstract] [Full Text]  
  • Risk, M., Shehu, A., Mao, J., Stocco, C. O., Goldsmith, L. T., Bowen-Shauver, J. M., Gibori, G. (2005). Cloning and Characterization of a 5' Regulatory Region of the Prolactin Receptor-Associated Protein/17{beta} Hydroxysteroid Dehydrogenase 7 Gene. Endocrinology 146: 2807-2816 [Abstract] [Full Text]  
  • Kumar, R., Gururaj, A. E., Vadlamudi, R. K., Rayala, S. K. (2005). The Clinical Relevance of Steroid Hormone Receptor Corepressors. Clin. Cancer Res. 11: 2822-2831 [Abstract] [Full Text]  
  • Kaneto, H., Nakatani, Y., Miyatsuka, T., Matsuoka, T.-a., Matsuhisa, M., Hori, M., Yamasaki, Y. (2005). PDX-1/VP16 Fusion Protein, Together With NeuroD or Ngn3, Markedly Induces Insulin Gene Transcription and Ameliorates Glucose Tolerance. Diabetes 54: 1009-1022 [Abstract] [Full Text]  
  • Huang, H., Rastegar, M., Bodner, C., Goh, S.-L., Rambaldi, I., Featherstone, M. (2005). MEIS C Termini Harbor Transcriptional Activation Domains That Respond to Cell Signaling. J. Biol. Chem. 280: 10119-10127 [Abstract] [Full Text]  
  • Berry, F. B., O'Neill, M. A., Coca-Prados, M., Walter, M. A. (2005). FOXC1 Transcriptional Regulatory Activity Is Impaired by PBX1 in a Filamin A-Mediated Manner. Mol. Cell. Biol. 25: 1415-1424 [Abstract] [Full Text]  
  • Mosley, A. L., Ozcan, S. (2004). The Pancreatic Duodenal Homeobox-1 Protein (Pdx-1) Interacts with Histone Deacetylases Hdac-1 and Hdac-2 on Low Levels of Glucose. J. Biol. Chem. 279: 54241-54247 [Abstract] [Full Text]  
  • Ogawa, S., Lozach, J., Jepsen, K., Sawka-Verhelle, D., Perissi, V., Sasik, R., Rose, D. W., Johnson, R. S., Rosenfeld, M. G., Glass, C. K. (2004). A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc. Natl. Acad. Sci. USA 101: 14461-14466 [Abstract] [Full Text]  
  • Selleri, L., DiMartino, J., van Deursen, J., Brendolan, A., Sanyal, M., Boon, E., Capellini, T., Smith, K. S., Rhee, J., Popperl, H., Grosveld, G., Cleary, M. L. (2004). The TALE Homeodomain Protein Pbx2 Is Not Essential for Development and Long-Term Survival. Mol. Cell. Biol. 24: 5324-5331 [Abstract] [Full Text]  
  • Stanojevic, V., Habener, J. F., Thomas, M. K. (2004). Pancreas Duodenum Homeobox-1 Transcriptional Activation Requires Interactions with p300. Endocrinology 145: 2918-2928 [Abstract] [Full Text]  
  • Liu, A., Desai, B. M., Stoffers, D. A. (2004). Identification of PCIF1, a POZ Domain Protein That Inhibits PDX-1 (MODY4) Transcriptional Activity. Mol. Cell. Biol. 24: 4372-4383 [Abstract] [Full Text]  
  • Hyman, C. A., Bartholin, L., Newfeld, S. J., Wotton, D. (2003). Drosophila TGIF Proteins Are Transcriptional Activators. Mol. Cell. Biol. 23: 9262-9274 [Abstract] [Full Text]  
  • Lu, Y., Goldenberg, I., Bei, L., Andrejic, J., Eklund, E. A. (2003). HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2. J. Biol. Chem. 278: 47792-47802 [Abstract] [Full Text]  
  • Tsuda, M., Takahashi, S., Takahashi, Y., Asahara, H. (2003). Transcriptional Co-activators CREB-binding Protein and p300 Regulate Chondrocyte-specific Gene Expression via Association with Sox9. J. Biol. Chem. 278: 27224-27229 [Abstract] [Full Text]  
  • Owens, B. M., Zhu, Y.-X., Suen, T.-C., Wang, P.-X., Greenblatt, J. F., Goss, P. E., Hawley, R. G. (2003). Specific homeodomain-DNA interactions are required for HOX11-mediated transformation. Blood 101: 4966-4974 [Abstract] [Full Text]  
  • Fujita, H., Fujii, R., Aratani, S., Amano, T., Fukamizu, A., Nakajima, T. (2003). Antithetic Effects of MBD2a on Gene Regulation. Mol. Cell. Biol. 23: 2645-2657 [Abstract] [Full Text]  
  • Baek, S. H., Kioussi, C., Briata, P., Wang, D., Nguyen, H. D., Ohgi, K. A., Glass, C. K., Wynshaw-Boris, A., Rose, D. W., Rosenfeld, M. G. (2003). Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Proc. Natl. Acad. Sci. USA 100: 3245-3250 [Abstract] [Full Text]  
  • Alexandre, C., Vincent, J.-P. (2003). Requirements for transcriptional repression and activation by Engrailed in Drosophila embryos. Development 130: 729-739 [Abstract] [Full Text]  
  • Troy, P. J., Daftary, G. S., Bagot, C. N., Taylor, H. S. (2003). Transcriptional Repression of Peri-Implantation EMX2 Expression in Mammalian Reproduction by HOXA10. Mol. Cell. Biol. 23: 1-13 [Abstract] [Full Text]  
  • Melloul, D., Marshak, S., Cerasi, E. (2002). Regulation of pdx-1 Gene Expression. Diabetes 51: S320-325 [Abstract] [Full Text]  
  • Owens, B. M., Hawley, R. G. (2002). HOX and Non-HOX Homeobox Genes in Leukemic Hematopoiesis. Stem Cells 20: 364-379 [Abstract] [Full Text]  
  • Li, X., Kimbrel, E. A., Kenan, D. J., MCDonnell, D. P. (2002). Direct Interactions between Corepressors and Coactivators Permit the Integration of Nuclear Receptor-Mediated Repression and Activation. Mol. Endocrinol. 16: 1482-1491 [Abstract] [Full Text]  
  • Li, X., McDonnell, D. P. (2002). 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. Mol. Cell. Biol. 22: 3663-3673 [Abstract] [Full Text]  
  • Jepsen, K., Rosenfeld, M. G. (2002). Biological roles and mechanistic actions of co-repressor complexes. J. Cell Sci. 115: 689-698 [Abstract] [Full Text]  
  • Choe, S.-K., Vlachakis, N., Sagerstrom, C. G. (2002). Meis family proteins are required for hindbrain development in the zebrafish. Development 129: 585-595 [Abstract] [Full Text]  
  • Asahara, H., Santoso, B., Guzman, E., Du, K., Cole, P. A., Davidson, I., Montminy, M. (2001). Chromatin-Dependent Cooperativity between Constitutive and Inducible Activation Domains in CREB. Mol. Cell. Biol. 21: 7892-7900 [Abstract] [Full Text]  
  • Guenther, M. G., Barak, O., Lazar, M. A. (2001). The SMRT and N-CoR Corepressors Are Activating Cofactors for Histone Deacetylase 3. Mol. Cell. Biol. 21: 6091-6101 [Abstract] [Full Text]  
  • Wotton, D., Knoepfler, P. S., Laherty, C. D., Eisenman, R. N., Massague, J. (2001). The Smad Transcriptional Corepressor TGIF Recruits mSin3. Cell Growth Differ. 12: 457-463 [Abstract] [Full Text]  
  • Kievit, P., Lauten, J. D., Maurer, R. A. (2001). Analysis of the Role of the Mitogen-Activated Protein Kinase in Mediating Cyclic-Adenosine 3',5'-Monophosphate Effects on Prolactin Promoter Activity. Mol. Endocrinol. 15: 614-624 [Abstract] [Full Text]  
  • Dutta, S., Gannon, M., Peers, B., Wright, C., Bonner-Weir, S., Montminy, M. (2001). PDX:PBX complexes are required for normal proliferation of pancreatic cells during development. Proc. Natl. Acad. Sci. USA 10.1073/pnas.031561298v1 [Abstract] [Full Text]  
  • Vlachakis, N, Choe, S., Sagerstrom, C. (2001). Meis3 synergizes with Pbx4 and Hoxb1b in promoting hindbrain fates in the zebrafish. Development 128: 1299-1312 [Abstract]  
  • Peshavaria, M., Cissell, M. A., Henderson, E., Petersen, H. V., Stein, R. (2000). The PDX-1 Activation Domain Provides Specific Functions Necessary for Transcriptional Stimulation in Pancreatic {beta}-Cells. Mol. Endocrinol. 14: 1907-1917 [Abstract] [Full Text]  
  • Saleh, M., Rambaldi, I., Yang, X.-J., Featherstone, M. S. (2000). Cell Signaling Switches HOX-PBX Complexes from Repressors to Activators of Transcription Mediated by Histone Deacetylases and Histone Acetyltransferases. Mol. Cell. Biol. 20: 8623-8633 [Abstract] [Full Text]  
  • BURKE, L. J., BANIAHMAD, A. (2000). Co-repressors 2000. FASEB J. 14: 1876-1888 [Abstract] [Full Text]  
  • Du, K., Asahara, H., Jhala, U. S., Wagner, B. L., Montminy, M. (2000). Characterization of a CREB Gain-of-Function Mutant with Constitutive Transcriptional Activity In Vivo. Mol. Cell. Biol. 20: 4320-4327 [Abstract] [Full Text]  
  • Guenther, M. G., Lane, W. S., Fischle, W., Verdin, E., Lazar, M. A., Shiekhattar, R. (2000). A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14: 1048-1057 [Abstract] [Full Text]  
  • Melhuish, T. A., Wotton, D. (2000). The Interaction of the Carboxyl Terminus-binding Protein with the Smad Corepressor TGIF Is Disrupted by a Holoprosencephaly Mutation in TGIF. J. Biol. Chem. 275: 39762-39766 [Abstract] [Full Text]  
  • Herzig, S., Fuzesi, L., Knepel, W. (2000). Heterodimeric Pbx-Prep1 Homeodomain Protein Binding to the Glucagon Gene Restricting Transcription in a Cell Type-dependent Manner. J. Biol. Chem. 275: 27989-27999 [Abstract] [Full Text]  
  • Kakizawa, T., Miyamoto, T., Ichikawa, K., Takeda, T., Suzuki, S., Mori, J.-i., Kumagai, M., Yamashita, K., Hashizume, K. (2001). Silencing Mediator for Retinoid and Thyroid Hormone Receptors Interacts with Octamer Transcription Factor-1 and Acts as a Transcriptional Repressor. J. Biol. Chem. 276: 9720-9725 [Abstract] [Full Text]  
  • Dusing, M. R., Florence, E. A., Wiginton, D. A. (2001). PDX-1 Is Required for Activation in Vivo from a Duodenum-specific Enhancer. J. Biol. Chem. 276: 14434-14442 [Abstract] [Full Text]  
  • Melhuish, T. A., Gallo, C. M., Wotton, D. (2001). TGIF2 Interacts with Histone Deacetylase 1 and Represses Transcription. J. Biol. Chem. 276: 32109-32114 [Abstract] [Full Text]  
  • Dutta, S., Gannon, M., Peers, B., Wright, C., Bonner-Weir, S., Montminy, M. (2001). PDX:PBX complexes are required for normal proliferation of pancreatic cells during development. Proc. Natl. Acad. Sci. USA 98: 1065-1070 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»