Regulation of the ERBB-2 Promoter by RBPJκ and NOTCH*

Within the human ERBB-2 gene promoter, a 100-base pair region 5′ to the TATA box enhances basal transcription 200-fold. Two palindromes present within this 100-base pair region are important for transcription. The palindrome binding protein was purified to homogeneity and found to be identical to RBPJκ, the mammalian homolog of Drosophila Suppressor of Hairless (Su(H)). Recombinant RBPJκ bound the ERBB-2 promoter with affinity comparable with that seen with well characterized RBPJκ binding sites. RBPJκ activated an ERBB-2palindrome-containing promoter in 293 cells. Because inDrosophila Su(H) acts downstream of NOTCH and because NOTCH·Su(H)/RBPJκ stimulates transcription from target promoters, NOTCH-IC, a constitutively active form of NOTCH, was tested for effects on the ERBB-2 palindrome. NOTCH-IC further increased RBPJκ-mediated transcription on wild type but not mutantERBB-2 palindrome. Thus, RBPJκ can activateERBB-2 transcription and serve as an anchor to mediate NOTCH function on the ERBB-2 gene.

[1]  K. Wood,et al.  Firefly luciferase gene: structure and expression in mammalian cells , 1987, Molecular and cellular biology.

[2]  F. Moreau-Gachelin,et al.  The Spi‐1/PU.1 and Spi‐B ets family transcription factors and the recombination signal binding protein RBP‐J kappa interact with an Epstein‐Barr virus nuclear antigen 2 responsive cis‐element. , 1994, The EMBO journal.

[3]  M. Hung,et al.  The retinoblastoma gene product suppresses neu oncogene-induced transformation via transcriptional repression of neu. , 1992, The Journal of biological chemistry.

[4]  L. Waltzer,et al.  The human J kappa recombination signal sequence binding protein (RBP‐J kappa) targets the Epstein‐Barr virus EBNA2 protein to its DNA responsive elements. , 1994, The EMBO journal.

[5]  M. Fortini,et al.  The suppressor of hairless protein participates in notch receptor signaling , 1994, Cell.

[6]  J. Posakony,et al.  Suppressor of Hairless, the Drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fates , 1992, Cell.

[7]  P. Ling,et al.  Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. , 1994, Science.

[8]  H. Okayama,et al.  High-efficiency transformation of mammalian cells by plasmid DNA. , 1987, Molecular and cellular biology.

[9]  J Vandekerckhove,et al.  Inhibition of the DNA-binding activity of Drosophila suppressor of hairless and of its human homolog, KBF2/RBP-J kappa, by direct protein-protein interaction with Drosophila hairless. , 1994, Genes & development.

[10]  C. Cordon-Cardo,et al.  Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. , 1990, Oncogene.

[11]  J. Hsieh,et al.  EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1 , 1994, Journal of virology.

[12]  T. Tanimura,et al.  Suppressor of hairless, the Drosophila homologue of RBP-J kappa, transactivates the neurogenic gene E(spl)m8. , 1995, Idengaku zasshi.

[13]  J. Sklar,et al.  TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms , 1991, Cell.

[14]  T. Honjo,et al.  A protein binding to the Jk recombination sequence of immunoglobulin genes contains a sequence related to the integrase motif , 1989, Nature.

[15]  P. Seeburg,et al.  Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. , 1985, Science.

[16]  S E Lux,et al.  Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Gill,et al.  A Heterodimeric Nuclear Protein Complex Binds Two Palindromic Sequences in the Proximal Enhancer of the Human erbB-2 Gene (*) , 1996, The Journal of Biological Chemistry.

[18]  J. Posakony,et al.  Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. , 1995, Genes & development.

[19]  W. Fischer,et al.  Microsequence Analysis of Proteins Purified by Gel Electrophoresis , 1991 .

[20]  T. Honjo,et al.  Epstein‐Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP‐J kappa, the homologue of Drosophila Suppressor of Hairless. , 1994, The EMBO journal.

[21]  M. Kraus,et al.  Overexpression of the EGF receptor‐related proto‐oncogene erbB‐2 in human mammary tumor cell lines by different molecular mechanisms. , 1987, The EMBO journal.

[22]  H. Weintraub,et al.  Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  F. Schweisguth,et al.  The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. , 1995, Genes & development.

[24]  F. Sarkar,et al.  c-erbB-2 promoter-specific DNA-binding protein isolated from human breast cancer tissues displays mitogenic activity. , 1994, The Journal of biological chemistry.

[25]  Christel Brou,et al.  Signalling downstream of activated mammalian Notch , 1995, Nature.

[26]  J. Hsieh,et al.  Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. , 1995, Science.

[27]  A. Ullrich,et al.  Human HER2 (neu) promoter: evidence for multiple mechanisms for transcriptional initiation , 1987, Molecular and cellular biology.

[28]  R. Weinberg,et al.  p185, a product of the neu proto-oncogene, is a receptorlike protein associated with tyrosine kinase activity , 1986, Molecular and cellular biology.

[29]  T. Williams,et al.  The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Hung,et al.  c-myc reverses neu-induced transformed morphology by transcriptional repression , 1991, Molecular and cellular biology.

[31]  M. Hung,et al.  Transcriptional repression of the neu protooncogene by the adenovirus 5 E1A gene products. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[32]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[33]  M. Hung,et al.  Identification and characterization of a novel enhancer for the rat neu promoter , 1991, Molecular and cellular biology.

[34]  T. Honjo,et al.  Human Jk recombination signal binding protein gene (IGKJRB): comparison with its mouse homologue. , 1993, Genomics.

[35]  S. Ishii,et al.  Characterization of the promoter region of the human c-erbB-2 protooncogene. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Honjo,et al.  The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor , 1994, Molecular and cellular biology.

[37]  M. Bosenberg,et al.  lag-1, a gene required for lin-12 and glp-1 signaling in Caenorhabditis elegans, is homologous to human CBF1 and Drosophila Su(H). , 1996, Development.

[38]  J. Cohen,et al.  Stage- and tissue-specific expression of the neu oncogene in rat development. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Coffin,et al.  Bacterial beta-galactosidase as a marker of Rous sarcoma virus gene expression and replication , 1985, Molecular and cellular biology.

[40]  T. Honjo,et al.  The Drosophila homolog of the immunoglobulin recombination signal-binding protein regulates peripheral nervous system development , 1992, Cell.

[41]  D. Gallahan,et al.  Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. , 1992, Genes & development.

[42]  T. Jessell,et al.  Diversity and Pattern in the Developing Spinal Cord , 1996, Science.

[43]  T. Honjo,et al.  Recognition sequence of a highly conserved DNA binding protein RBP-Jx , 1994 .

[44]  M. Hung,et al.  Cloning and characterization of the mouse neu promoter. , 1992, Oncogene.

[45]  H. Weintraub,et al.  The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. , 1994, Development.

[46]  G. Gill,et al.  Structural features of the 5' region of the human erbB-2 gene. , 1993, Gene.

[47]  E. Kieff,et al.  The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the J kappa recombination signal binding protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[49]  Y. Chen,et al.  Positive and negative regulatory elements in the human erbB-2 gene promoter. , 1994, Oncogene.

[50]  T. Honjo,et al.  Biochemical and immunological characterization of the DNA binding protein (RBP-J kappa) to mouse J kappa recombination signal sequence. , 1992, Journal of biochemistry.

[51]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.