Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells

We describe a novel gene, Blimp-1 (for B lymphocyte-induced maturation protein), transcripts of which are rapidly induced during the differentiation of B lymphocytes into immunoglobulin secretory cells and whose expression is characteristic of late B and plasma cell lines. The 856 amino acid open reading frame contains five Krüppel-type zinc finger motifs and proline-rich and acidic regions similar to those of known transcription factors. Serological studies show an approximately 100 kd protein that localizes to the nucleus. Stable or transient transfection of Blimp-1 into B cell lymphoma lines leads to the expression of many of the phenotypic changes associated with B cell differentiation into an early plasma cell stage, including induction of J chain message and immunoglobulin secretion, up-regulation of Syndecan-1, and increased cell size and granularity. Thus, Blimp-1 appears to be a pleiotropic regulatory factor capable of at least partially driving the terminal differentiation of B cells.

[1]  P Berg,et al.  Electroporation for the efficient transfection of mammalian cells with DNA. , 1987, Nucleic acids research.

[2]  P. Mckeever,et al.  Membrane immunoglobulins of spontaneous B lymphomas of aged BALB/c mice , 1981, European journal of immunology.

[3]  D H Sachs,et al.  Establishment and characterization of BALB/c lymphoma lines with B cell properties. , 1979, Journal of immunology.

[4]  B. Beutler,et al.  Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. Randall,et al.  The biological effects of IgM hexamer formation , 1990, European journal of immunology.

[6]  D. Melton,et al.  Xfin: an embryonic gene encoding a multifingered protein in Xenopus. , 1987, The EMBO journal.

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

[8]  R. Krumlauf,et al.  The zinc finger gene Krox20 regulates HoxB2 (Hox2.8) during hindbrain segmentation , 1993, Cell.

[9]  Tony Hunter,et al.  The regulation of transcription by phosphorylation , 1992, Cell.

[10]  M. Ptashne.  How eukaryotic transcriptional activators work , 1988, Nature.

[11]  S. O’Brien,et al.  The GLI-Kruppel family of human genes , 1988, Molecular and cellular biology.

[12]  V. Sukhatme,et al.  Differential expression of a zinc finger-encoding gene in response to positive versus negative signaling through receptor immunoglobulin in murine B lymphocytes , 1989, Molecular and cellular biology.

[13]  P. Lemaire,et al.  Characterization of a mouse multigene family that encodes zinc finger structures , 1988, Molecular and cellular biology.

[14]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[15]  Kevin Struhl,et al.  Structural and functional characterization of the short acidic transcriptional activation region of yeast GCN4 protein , 1988, Nature.

[16]  M. Davis,et al.  Expression of T cell antigen receptor heterodimers in a lipid-linked form. , 1990, Science.

[17]  H. Karasuyama,et al.  Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors , 1988, European journal of immunology.

[18]  J. Devereux,et al.  A comprehensive set of sequence analysis programs for the VAX , 1984, Nucleic Acids Res..

[19]  P. Sigler,et al.  Acid blobs and negative noodles , 1988, Nature.

[20]  Helen M. Blau,et al.  Genetic complementation reveals a novel regulatory role for 3′ untranslated regions in growth and differentiation , 1993, Cell.

[21]  M. Lieber,et al.  Developmental stage specificity of the lymphoid V(D)J recombination activity. , 1987, Genes & development.

[22]  H. Jäckle,et al.  Molecular genetics of Krüppel, a gene required for segmentation of the Drosophila embryo , 1985, Nature.

[23]  M. Shulman,et al.  IgM--molecular requirements for its assembly and function. , 1989, Immunology today.

[24]  S. Tonegawa.  Somatic generation of antibody diversity , 1983, Nature.

[25]  N. Archidiacono,et al.  Isolation and expression analysis of a human zinc finger gene (ZNF41) located on the short arm of the X chromosome. , 1991, Genomics.

[26]  H. Jäckle,et al.  A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Krüppel, a Drosophila segmentation gene , 1986, Cell.

[27]  H. Jäckle,et al.  Structural homology of the product of the Drosophila Krüppel gene with Xenopus transcription factor IIIA , 1986, Nature.

[28]  Jun Ma,et al.  Deletion analysis of GAL4 defines two transcriptional activating segments , 1987, Cell.

[29]  K. Struhl,et al.  Functional dissection of a eukaryotic transcriptional activator protein, GCN4 of Yeast , 1986, Cell.

[30]  P. Ralph,et al.  Murine B cell leukemia line with inducible surface immunoglobulin expression. , 1978, Journal of immunology.

[31]  M. Ptashne,et al.  Transcription in yeast activated by a putative amphipathic α helix linked to a DNA binding unit , 1987, Nature.

[32]  D. Smith,et al.  Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. , 1988, Gene.

[33]  Robert K. Davis,et al.  The myoD gene family: nodal point during specification of the muscle cell lineage. , 1991, Science.

[34]  R. Sanderson,et al.  B lymphocytes express and lose syndecan at specific stages of differentiation. , 1989, Cell regulation.

[35]  M. Davis,et al.  Expression of a class II major histocompatibility complex (MHC) heterodimer in a lipid-linked form with enhanced peptide/soluble MHC complex formation at low pH , 1991, The Journal of experimental medicine.

[36]  K. Rajewsky.  Early and late B-cell development in the mouse. , 1992 .

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

[38]  N. Fedoroff,et al.  A general method for the large-scale isolation of polysomes and messenger RNA applied to MOPC 21 mouse myeloma tumors. , 1977, Analytical biochemistry.

[39]  C. Amemiya,et al.  Clustered organization of homologous KRAB zinc‐finger genes with enhanced expression in human T lymphoid cells. , 1993, The EMBO journal.

[40]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[41]  R. Lynch,et al.  The physiology of B cells as studied with tumor models. , 1986, Annual review of immunology.

[42]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[43]  E. Harlow,et al.  Antibodies: A Laboratory Manual , 1988 .

[44]  P. Gruss,et al.  Specific and ubiquitous expression of different Zn finger protein genes in the mouse. , 1988, Nucleic acids research.

[45]  P. Y. Chou,et al.  Conformational parameters for amino acids in helical, beta-sheet, and random coil regions calculated from proteins. , 1974, Biochemistry.

[46]  K. Lin,et al.  An efficient method to purify active eukaryotic proteins from the inclusion bodies in Escherichia coli. , 1991, BioTechniques.

[47]  J. Trowsdale,et al.  A mouse zinc finger gene which is transiently expressed during spermatogenesis. , 1990, The EMBO journal.

[48]  F. Melchers,et al.  Ontogeny of murine B lymphocytes: development of Ig synthesis and of reactivities to mitogens and to anti-Ig-antibodies. , 1977, Cold Spring Harbor symposia on quantitative biology.

[49]  E. A. O'neill,et al.  The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain , 1989, Cell.

[50]  Harold Weintraub,et al.  The MyoD family and myogenesis: Redundancy, networks, and thresholds , 1993, Cell.

[51]  A. Bairoch.  PROSITE: a dictionary of sites and patterns in proteins. , 1991, Nucleic acids research.

[52]  H. Kawasaki,et al.  Regulation of activity of calcium activated neutral protease. , 1988, Advances in enzyme regulation.

[53]  P. Y. Chou,et al.  Prediction of protein conformation. , 1974, Biochemistry.

[54]  M. Blackman,et al.  A model system for peptide hormone action in differentiation: Interleukin 2 induces a B lymphoma to transcribe the J chain gene , 1986, Cell.

[55]  S. Johnston,et al.  Genetic evidence that an activation domain of GAL4 does not require acidity and may form a β sheet , 1993, Cell.

[56]  J. Bieker,et al.  A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins , 1993, Molecular and cellular biology.

[57]  T. Kodadek,et al.  The acidic activation domains of the GCN4 and GAL4 proteins are not α helical but form β sheets , 1993, Cell.

[58]  T. Hada,et al.  B cell response pathways regulated by IL-5 and IL-2. Secretory microH chain-mRNA and J chain mRNA expression are separately controlled events. , 1989, Journal of immunology.

[59]  M. Rechsteiner,et al.  Regulation of enzyme levels by proteolysis: the role of pest regions. , 1988, Advances in enzyme regulation.