Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements

The Fos-Jun complex has been shown to activate transcription through the regulatory element known as the AP-1 binding site. We show that Fos down regulates several immediate-early genes (c-fos, Egr-1, and Egr-2) after mitogenic stimulation. Specifically, we demonstrate that the target for this repression is a sequence of the form CC(A/T)6GG, also known as a CArG box. Whereas Fos bound to the AP-1 site through a domain rich in basic amino acids and associated with Jun via a leucine zipper interaction, mutant Fos proteins lacking these structures were still capable of causing repression. Furthermore, Jun neither enhanced nor inhibited down regulation by Fos. Critical residues required for repression are located within the C-terminal 27 amino acids of c-Fos, since v-Fos and C-terminal truncations of c-Fos did not down regulate. In addition, transfer of 180 c-Fos C-terminal amino acids to Jun conferred upon it the ability to repress. Finally, Fra-1, a Fos-related protein which has striking similarity to Fos in its C-terminal 40 amino acids, also down regulated Egr-1 expression. Thus, Fos is a transcriptional regulator that can activate or repress gene expression by way of two separate functional domains that act on distinct regulatory elements.

[1]  R. Koski,et al.  Identification and characterization of the Egr-1 gene product, a DNA-binding zinc finger protein induced by differentiation and growth signals , 1990, Molecular and cellular biology.

[2]  V. Rangnekar,et al.  The serum and TPA responsive promoter and intron-exon structure of EGR2, a human early growth response gene encoding a zinc finger protein. , 1990, Nucleic acids research.

[3]  M. Sheng,et al.  The inner core of the serum response element mediates both the rapid induction and subsequent repression of c-fos transcription following serum stimulation. , 1990, Genes & development.

[4]  D. Luk,et al.  Expression and purification of the leucine zipper and DNA-binding domains of Fos and Jun: both Fos and Jun contact DNA directly. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[5]  James I. Morgan,et al.  Stimulus-transcription coupling in neurons: role of cellular immediate-early genes , 1989, Trends in Neurosciences.

[6]  T. Curran,et al.  Regulation of proenkephalin by Fos and Jun. , 1989, Science.

[7]  F. C. Lucibello,et al.  Trans-repression of the mouse c-fos promoter: A novel mechanism of fos-mediated trans-regulation , 1989, Cell.

[8]  D. Nathans,et al.  DNA binding site of the growth factor-inducible protein Zif268. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Nathans,et al.  Functional serum response elements upstream of the growth factor-inducible gene zif268 , 1989, Molecular and cellular biology.

[10]  A. Schönthal,et al.  Autoregulation of fos: the dyad symmetry element as the major target of repression. , 1989, The EMBO journal.

[11]  J. Sonnenberg,et al.  Dynamic alterations occur in the levels and composition of transcription factor AP-1 complexes after seizure , 1989, Neuron.

[12]  Andrew J. Cole,et al.  Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation , 1989, Nature.

[13]  L. Schmidt,et al.  Negative regulation of serum-responsive enhancer elements , 1989, Nature.

[14]  A. Nordheim,et al.  Occupation of the c-fos serum response element in vivo by a multi-protein complex is unaltered by growth factor induction , 1989, Nature.

[15]  B. Franza,et al.  Two distinct cellular phosphoproteins bind to the c‐fos serum response element. , 1989, The EMBO journal.

[16]  T. Curran,et al.  Parallel association of Fos and Jun leucine zippers juxtaposes DNA binding domains. , 1989, Science.

[17]  M. Zerial,et al.  The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity. , 1989, The EMBO journal.

[18]  A. Nordheim,et al.  The ability of a ternary complex to form over the serum response element correlates with serum inducibility of the human c-fos promoter , 1989, Cell.

[19]  L. Kedes,et al.  The sarcomeric actin CArG-binding factor is indistinguishable from the c-fos serum response factor , 1989, Molecular and cellular biology.

[20]  M. Zerial,et al.  Structure, chromosome location, and expression of the mouse zinc finger gene Krox-20: multiple gene products and coregulation with the proto-oncogene c-fos , 1989, Molecular and cellular biology.

[21]  Richard Treisman,et al.  Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element , 1988, Cell.

[22]  I. Verma,et al.  Direct interaction between fos and jun nuclear oncoproteins: role of the 'leucine zipper' domain , 1988, Nature.

[23]  T. Kouzarides,et al.  The role of the leucine zipper in the fos–jun interaction , 1988, Nature.

[24]  Michael E. Greenberg,et al.  c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities , 1988, Cell.

[25]  Y. Nakabeppu,et al.  DNA binding activities of three murine Jun proteins: Stimulation by Fos , 1988, Cell.

[26]  Peter Angel,et al.  The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1 , 1988, Cell.

[27]  B. Franza,et al.  Fos and Jun bind cooperatively to the AP-1 site: reconstitution in vitro. , 1988, Genes & development.

[28]  R. Treisman,et al.  Fos C‐terminal mutations block down‐regulation of c‐fos transcription following serum stimulation. , 1988, The EMBO journal.

[29]  T. Curran,et al.  Activation of the transforming potential of the human fos proto-oncogene requires message stabilization and results in increased amounts of partially modified fos protein , 1988, Molecular and cellular biology.

[30]  L. Lau,et al.  A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc finger" sequences. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. Lau,et al.  A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Nathans,et al.  Induction of protooncogene c-jun by serum growth factors. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Rowley,et al.  Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Anindya Dutta,et al.  Phosphorylation of serum response factor, a factor that binds to the serum response element of the c-FOS enhancer. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[35]  V. Sukhatme,et al.  5' flanking sequence and genomic structure of Egr-1, a murine mitogen inducible zinc finger encoding gene. , 1988, Nucleic acids research.

[36]  I. Verma,et al.  Induction of proto-oncogene JUN/AP-1 by serum and TPA , 1988, Nature.

[37]  T. Hunter,et al.  The c-fos protein interacts with c-Jun AP-1 to stimulate transcription of AP-1 responsive genes , 1988, Cell.

[38]  M. Yaniv,et al.  Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts , 1988, Nature.

[39]  I. Verma,et al.  Transcriptional autoregulation of the proto-oncogene fos , 1988, Nature.

[40]  P. Lemaire,et al.  Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. McKnight,et al.  The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. , 1988, Science.

[42]  R. Tjian,et al.  Fos-associated protein p39 is the product of the jun proto-oncogene. , 1988, Science.

[43]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[44]  T. Curran,et al.  fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen , 1988, Molecular and cellular biology.

[45]  J. Milbrandt.  Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene , 1988, Neuron.

[46]  Eileen D. Adamson,et al.  A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization , 1988, Cell.

[47]  B. Franza,et al.  The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites. , 1988, Science.

[48]  B. Spiegelman,et al.  Common DNA binding site for Fos protein complexesand transcription factor AP-1 , 1988, Cell.

[49]  M. Zerial,et al.  A gene encoding a protein with zinc fingers is activated during G0/G1 transition in cultured cells. , 1988, The EMBO journal.

[50]  R. Tjian,et al.  Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. , 1987, Science.

[51]  J. Milbrandt,et al.  A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. , 1987, Science.

[52]  L. Kedes,et al.  Duplicated CArG box domains have positive and mutually dependent regulatory roles in expression of the human alpha-cardiac actin gene , 1987, Molecular and cellular biology.

[53]  B. Luckow,et al.  CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements , 1987, Nucleic Acids Res..

[54]  T. Curran,et al.  Mapping patterns of c-fos expression in the central nervous system after seizure. , 1987, Science.

[55]  I. Verma,et al.  Modification of fos proteins: phosphorylation of c-fos, but not v-fos, is stimulated by 12-tetradecanoyl-phorbol-13-acetate and serum , 1987, Molecular and cellular biology.

[56]  P. Vogt,et al.  Avian sarcoma virus 17 carries the jun oncogene. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Greenberg,et al.  Mutation of the c-fos gene dyad symmetry element inhibits serum inducibility of transcription in vivo and the nuclear regulatory factor binding in vitro , 1987, Molecular and cellular biology.

[58]  L. Lau,et al.  Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[59]  T. Jenuwein,et al.  Structure-function analysis of fos protein: A single amino acid change activates the immortalizing potential of v-fos , 1987, Cell.

[60]  R. Weinberg,et al.  Multiple protein-binding sites in the 5'-flanking region regulate c-fos expression , 1986, Molecular and cellular biology.

[61]  T. Curran,et al.  Barium modulates c-fos expression and post-translational modification. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Richard Treisman,et al.  Identification of a protein-binding site that mediates transcriptional response of the c-fos gene to serum factors , 1986, Cell.

[63]  James I. Morgan,et al.  Role of ion flux in the control of c-fos expression , 1986, Nature.

[64]  L. Kedes,et al.  Upstream regions of the human cardiac actin gene that modulate its transcription in muscle cells: presence of an evolutionarily conserved repeated motif , 1986, Molecular and cellular biology.

[65]  L. Lau,et al.  Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. , 1985, The EMBO journal.

[66]  M. Greenberg,et al.  Nerve growth factor and epidermal growth factor induce rapid transient changes in proto-oncogene transcription in PC12 cells. , 1985, The Journal of biological chemistry.

[67]  I. Verma,et al.  Induction of the proto-oncogene fos by nerve growth factor. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[68]  T. Curran,et al.  Superinduction of c-fos by nerve growth factor in the presence of peripherally active benzodiazepines. , 1985, Science.

[69]  Michael E. Greenberg,et al.  Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene , 1984, Nature.

[70]  T. Curran,et al.  FBR murine osteosarcoma virus. I. Molecular analysis and characterization of a 75,000-Da gag-fos fusion product. , 1984, Virology.

[71]  I. Verma,et al.  Viral and cellular fos proteins: A comparative analysis , 1984, Cell.

[72]  T. Curran,et al.  c-fos protein can induce cellular transformation: A novel mechanism of activation of a cellular oncogene , 1984, Cell.

[73]  Brent H. Cochran,et al.  Molecular cloning of gene sequences regulated by platelet-derived growth factor , 1983, Cell.

[74]  R. Roeder,et al.  Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. , 1983, Nucleic acids research.

[75]  B. Howard,et al.  Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells , 1982, Molecular and cellular biology.

[76]  T. Curran,et al.  Candidate product of the FBJ murine osteosarcoma virus oncogene: characterization of a 55,000-dalton phosphoprotein , 1982, Journal of virology.

[77]  A. Curran.  fra-1: aSerum-Inducible, Cellular Immediate-Early GeneThat Encodes aFos-Related Antigen , 1988 .

[78]  H R Herschman,et al.  Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. , 1987, Oncogene.

[79]  T. Curran,et al.  Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro. , 1987, Oncogene.

[80]  T. Jenuwein,et al.  Isolation and structural analysis of a biologically active chicken c-fos cDNA: identification of evolutionarily conserved domains in fos protein. , 1987, Oncogene.

[81]  T. Curran,et al.  Induction of c-fos gene and protein by growth factors precedes activation of c-myc , 1984, Nature.

[82]  Jonathan A. Cooper,et al.  Platelet-derived growth factor induces rapid but transient expression of the c-fos gene and protein , 1984, Nature.

[83]  E. Shooter,et al.  The biology and mechanism of action of nerve growth factor. , 1982, Annual review of biochemistry.