Transforming Growth Factor-β-stimulated Clone-22 Is a Member of a Family of Leucine Zipper Proteins That Can Homo- and Heterodimerize and Has Transcriptional Repressor Activity*

TGF-β-stimulatedclone-22 (TSC-22) encodes a leucine zipper-containing protein that is highly conserved during evolution. Two homologues are known that share a similar leucine zipper domain and another conserved domain (designated the TSC box). Only limited data are available on the function of TSC-22 and its homologues. TSC-22 is transcriptionally up-regulated by many different stimuli, including anti-cancer drugs and growth inhibitors, and recent data suggest that TSC-22 may play a suppressive role in tumorigenesis. In this paper we show that TSC-22 forms homodimers via its conserved leucine zipper domain. Using a yeast two-hybrid screen, we identified a TSC-22 homologue (THG-1) as heterodimeric partner. Furthermore, we report the presence of two more mammalian family members with highly conserved leucine zippers and TSC boxes. Interestingly, both TSC-22 and THG-1 have transcriptional repressor activity when fused to a heterologous DNA-binding domain. The repressor activity of TSC-22 appears sensitive for promoter architecture, but not for the histone deacetylase inhibitor trichostatin A. Mutational analysis showed that this repressor activity resides in the non-conserved regions of the protein and is enhanced by the conserved dimerization domain. Our results suggest that TSC-22 belongs to a family of leucine zipper-containing transcription factors that can homodimerize and heterodimerize with other family members and that at least two TSC-22 family members may be repressors of transcription.

[1]  J. Welsh,et al.  Non-stoichiometric reduced complexity probes for cDNA arrays. , 1998, Nucleic acids research.

[2]  D. Dean,et al.  Rb Interacts with Histone Deacetylase to Repress Transcription , 1998, Cell.

[3]  L. Magnaghi-Jaulin,et al.  Retinoblastoma protein represses transcription by recruiting a histone deacetylase , 1998, Nature.

[4]  Tony Kouzarides,et al.  Retinoblastoma protein recruits histone deacetylase to repress transcription , 1998, Nature.

[5]  H. Yoshida,et al.  Down-regulation of TSC-22 (transforming growth factor beta-stimulated clone 22) markedly enhances the growth of a human salivary gland cancer cell line in vitro and in vivo. , 1998, Cancer research.

[6]  R. Jaenicke,et al.  Solution Structure of Porcine Delta Sleep-inducing Peptide Immunoreactive Peptide A Homolog of the ShortsightedGene Product* , 1997, The Journal of Biological Chemistry.

[7]  C. Riccardi,et al.  A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. , 1997, Immunity.

[8]  L. Dobens,et al.  The Drosophila bunched gene is a homologue of the growth factor stimulated mammalian TSC-22 sequence and is required during oogenesis , 1997, Mechanisms of Development.

[9]  B. van der Burg,et al.  Novel Progesterone Target Genes Identified by an Improved Differential Display Technique Suggest That Progestin-induced Growth Inhibition of Breast Cancer Cells Coincides with Enhancement of Differentiation* , 1997, The Journal of Biological Chemistry.

[10]  Wen‐Ming Yang,et al.  Histone Deacetylases Associated with the mSin3 Corepressor Mediate Mad Transcriptional Repression , 1997, Cell.

[11]  S. Schreiber,et al.  Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase , 1997, Cell.

[12]  Stuart L Schreiber,et al.  Histone Deacetylase Activity Is Required for Full Transcriptional Repression by mSin3A , 1997, Cell.

[13]  C. Glass,et al.  A complex containing N-CoR, mSln3 and histone deacetylase mediates transcriptional repression , 1997, nature.

[14]  W. Forssmann,et al.  hDIP--a potential transcriptional regulator related to murine TSC-22 and Drosophila shortsighted (shs)--is expressed in a large number of human tissues. , 1996, Biochimica et biophysica acta.

[15]  S. Ohta,et al.  Molecular cloning and characterization of a transcription factor for the C-type natriuretic peptide gene promoter. , 1996, European journal of biochemistry.

[16]  Hans Clevers,et al.  XTcf-3 Transcription Factor Mediates β-Catenin-Induced Axis Formation in Xenopus Embryos , 1996, Cell.

[17]  S. Taviaux,et al.  Cloning of the Human Homologue of the TGFβ-Stimulated Clone 22 Gene , 1996 .

[18]  S. Schreiber,et al.  A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p , 1996, Science.

[19]  C. Auffray,et al.  The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. , 1996, Genomics.

[20]  E. Kalkhoven,et al.  Negative Interaction between the RelA(p65) Subunit of NF-B and the Progesterone Receptor (*) , 1996, The Journal of Biological Chemistry.

[21]  G. Folkers,et al.  Adenovirus E1A functions as a cofactor for retinoic acid receptor beta (RAR beta) through direct interaction with RAR beta , 1995, Molecular and cellular biology.

[22]  G. Folkers,et al.  Activation Function 1 of Retinoic Acid Receptor β2 Is an Acidic Activator Resembling VP16 (*) , 1995, The Journal of Biological Chemistry.

[23]  G. Rubin,et al.  Shortsighted acts in the decapentaplegic pathway in Drosophila eye development and has homology to a mouse TGF-beta-responsive gene. , 1995, Development.

[24]  J. Bischoff,et al.  Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Raida,et al.  A novel 77-residue peptide from porcine brain contains a leucine-zipper motif and is recognized by an antiserum to delta-sleep-inducing peptide. , 1993, European journal of biochemistry.

[26]  J. Craig Venter,et al.  Rapid cDNA sequencing (expressed sequence tags) from a directionally cloned human infant brain cDNA library , 1993, Nature Genetics.

[27]  C. Vinson,et al.  Dimerization specificity of the leucine zipper-containing bZIP motif on DNA binding: prediction and rational design. , 1993, Genes & development.

[28]  K. Nose,et al.  Isolation of a gene encoding a putative leucine zipper structure that is induced by transforming growth factor beta 1 and other growth factors. , 1992, The Journal of biological chemistry.

[29]  D. Ron,et al.  CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. , 1992, Genes & development.

[30]  C. Clarke,et al.  Progestin regulation of cellular proliferation. , 1990, Endocrine reviews.

[31]  Harold Weintraub,et al.  The protein Id: A negative regulator of helix-loop-helix DNA binding proteins , 1990, Cell.

[32]  H. Yoshida,et al.  Induction of TSC-22 by treatment with a new anti-cancer drug, vesnarinone, in a human salivary gland cancer cell. , 1998, British Journal of Cancer.

[33]  I. Cowell,et al.  Repression versus activation in the control of gene transcription. , 1994, Trends in biochemical sciences.