Alternative splicing of fosB transcripts results in differentially expressed mRNAs encoding functionally antagonistic proteins.

We show that serum-stimulated fibroblasts transiently express two different forms of fosB mRNA, which are generated by alternative splicing of the transcript from a single gene. In addition to the known long form (fosB-L), encoding a protein of 338 amino acids (FosB-L), a second shorter form (fosB-S) with a deletion of 140 bp was detected. This deletion creates a stop codon 3' to the leucine repeat, giving rise to a protein of 237 amino acids (FosB-S) lacking the carboxyl terminus of FosB-L. Only the long FosB form efficiently induces transformation in mouse and rat fibroblast cell lines and trans-represses the c-fos promoter. Both of these functions are suppressed by coexpressed FosB-S. Upon serum stimulation, maximum expression of the oncogenic fosB-L form precedes the expression of the antagonistic fosB-S form, indicating a new mechanisms regulating the action of members of the Fos family. However, FosB-L and FosB-S do not differ in all trans-regulatory properties: Trans-activation of a 5x TRE-CAT reporter construct in HeLa and NIH-3T3 cells was found with both FosB forms. These observations suggest a correlation between fosB-induced transformation and trans-repression, thus pointing to different mechanisms involved in transformation by fosB and c-fos/v-fos.

[1]  Y. Nakabeppu,et al.  A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity , 1991, Cell.

[2]  Stephan Gebel,et al.  Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone , 1990, Cell.

[3]  M. Clarke,et al.  Differentiation of mouse erythroleukemia cells enhanced by alternatively spliced c-myb mRNA. , 1990, Science.

[4]  F. C. Lucibello,et al.  Mutual transrepression of Fos and the glucocorticoid receptor: involvement of a functional domain in Fos which is absent in FosB. , 1990, The EMBO journal.

[5]  M. Schuermann.  An expression vector system for stable expression of oncogenes. , 1990, Nucleic acids research.

[6]  M. Beato,et al.  Tissue-specific expression, hormonal regulation and 5'-flanking gene region of the rat Clara cell 10 kDa protein: comparison to rabbit uteroglobin. , 1990, Nucleic acids research.

[7]  H. Iba,et al.  Isolation and characterization of fra-2, an additional member of the fos gene family. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

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

[9]  N. Nomura,et al.  Isolation of human fos-related genes and their expression during monocyte-macrophage differentiation. , 1990, Oncogene.

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

[11]  J. Minna,et al.  jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun , 1989, Cell.

[12]  A. Levinson,et al.  Expression of the H-ras proto-oncogene is controlled by alternative splicing , 1989, Cell.

[13]  R. Tjian,et al.  Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. , 1989, Science.

[14]  M. Yaniv,et al.  Characterization of junD: a new member of the jun proto‐oncogene family. , 1989, The EMBO journal.

[15]  R. Müller,et al.  Two functionally different regions in Fos are required for the sequence-specific DNA interaction of the Fos/Jun protein complex , 1989, Nature.

[16]  R. Tjian,et al.  Leucine repeats and an adjacent DNA binding domain mediate the formation of functional cFos-cJun heterodimers. , 1989, Science.

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

[18]  D. Nathans,et al.  jun-D: a third member of the jun gene family. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[19]  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.

[20]  T. Jenuwein,et al.  The leucine repeat motif in Fos protein mediates complex formation with Jun/AP-1 and is required for transformation , 1989, Cell.

[21]  B. Franza,et al.  The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes. , 1989, Genes & development.

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

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

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

[26]  B. Franza,et al.  Fos and jun: The AP-1 connection , 1988, Cell.

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

[28]  I. Verma,et al.  fos-associated cellular p39 is related to nuclear transcription factor AP-1 , 1988, Cell.

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

[30]  A. Schönthal,et al.  Requirement for fos gene expression in the transcriptional activation of collagenase by other oncogenes and phorbol esters , 1988, Cell.

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

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

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

[34]  R. Bravo,et al.  Complexity of the early genetic response to growth factors in mouse fibroblasts , 1988, Molecular and cellular biology.

[35]  D. Baltimore,et al.  Four murine c-abl mRNAs arise by usage of two transcriptional promoters and alternative splicing. , 1988, Oncogene.

[36]  L. Lau,et al.  A gene activated by growth factors is related to the oncogene v-jun. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[37]  K. Mullis,et al.  Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. , 1988, Science.

[38]  J. Brugge,et al.  The structurally distinct form of pp60c-src detected in neuronal cells is encoded by a unique c-src mRNA , 1987, Molecular and cellular biology.

[39]  G. Superti-Furga,et al.  Mutually exclusive interaction of the CCAAT-binding factor and of a displacement protein with overlapping sequences of a histone gene promoter , 1987, Cell.

[40]  R. Tjian,et al.  Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements , 1987, Cell.

[41]  M. Karin,et al.  Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor , 1987, Cell.

[42]  L. Wang,et al.  Regulation of the expression of proto-oncogene c-src by alternative RNA splicing in chicken skeletal muscle. , 1987, Oncogene research.

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

[44]  A. Schönthal,et al.  Posttranscriptional regulation of c-fos mRNA expression. , 1987, Nucleic acids research.

[45]  G. Daley,et al.  Alternative 5′ exons in c-abl mRNA , 1986, Cell.

[46]  T. Curran,et al.  Removal of a 67-base-pair sequence in the noncoding region of protooncogene fos converts it to a transforming gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[47]  T. Jenuwein,et al.  Extended life span and tumorigenicity of nonestablished mouse connective tissue cells transformed by the fos oncogene of FBR-MuSV , 1985, Cell.

[48]  E. Chen,et al.  Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. , 1985, DNA.

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

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

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

[52]  P. Leder,et al.  Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor , 1983, Cell.

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

[54]  I. Verma,et al.  Transcription of c-onc genes c-rasKi and c-fms during mouse development , 1983, Molecular and cellular biology.

[55]  I. Pastan,et al.  The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[56]  P. Thomas,et al.  Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[57]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[58]  P. Herrlich,et al.  'Nuclear' oncogenes convert extracellular stimuli into changes in the genetic program. , 1989, Trends in genetics : TIG.

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

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