The HRAS1 gene cluster: two upstream regions recognizing transcripts and a third encoding a gene with a leucine zipper domain.

We have cloned and characterized a 55-kb region of DNA surrounding HRAS1. It contains a cluster of two, and possibly three, genes associated with CpG islands within the 32 kb immediately upstream of HRAS1. We have sequenced cDNAs representing one of these genes, provisionally designated HRC1. The locus, which is located 29 kb upstream of HRAS1, is divergently transcribed. HRC1 cDNA probe recognizes fragments on Southern blots of DNA from other vertebrate species. In human DNA, multiple homologous fragments are detected in addition to the predicted ones containing HRC1. Therefore, this locus may represent a member of an evolutionarily conserved gene family. HRC1 expression is upregulated with HRAS1 in the EJ bladder carcinoma cell line, suggesting the possibility of coordinate regulation. The deduced translational product of the longest open reading frame (1119 nucleotides, 373 amino acids) predicts a protein with regions rich in glutamine and proline and a region similar to the helix-loop-helix motif adjacent to a carboxy-terminal leucine zipper dimerization motif with four heptad repeats. Alternate splicing of terminal exons occurs, resulting in the truncation of one proline-rich domain and preservation of the leucine zipper. Thus, a biologically important region of chromosome 11p consists of a gene cluster. At least one of these genes, in addition to HRAS1, may be involved in regulation of cell growth or differentiation.

[1]  Stephen M. Mount,et al.  A catalogue of splice junction sequences. , 1982, Nucleic acids research.

[2]  E. Southern.  Detection of specific sequences among DNA fragments separated by gel electrophoresis. , 1975, Journal of molecular biology.

[3]  J. Posakony,et al.  extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins , 1990, Cell.

[4]  A. Bird,et al.  Use of restriction enzymes to detect potential gene sequences in mammalian DNA , 1987, Nature.

[5]  M. Israel,et al.  A human Id-like helix-loop-helix protein expressed during early development. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Nicolas Mermod,et al.  A family of human CCAAT-box-binding proteins active in transcription and DNA replication: cloning and expression of multiple cDNAs , 1988, Nature.

[7]  S. Tapscott,et al.  Functional antagonism between c-Jun and MyoD proteins: A direct physical association , 1992, Cell.

[8]  P. Y. Chou,et al.  Empirical predictions of protein conformation. , 1978, Annual review of biochemistry.

[9]  K. Calame,et al.  A dominant negative form of transcription activator mTFE3 created by differential splicing. , 1991, Science.

[10]  R. Roeder,et al.  The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. , 1990, Genes & development.

[11]  J. Garnier,et al.  Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. , 1978, Journal of molecular biology.

[12]  C. Richardson,et al.  DNA sequence analysis with a modified bacteriophage T7 DNA polymerase. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[13]  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.

[14]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[15]  B. Weissman,et al.  Suppression of tumorigenicity in Wilms tumor by the p15.5-p14 region of chromosome 11. , 1991, Science.

[16]  J. Visvader,et al.  Helix-loop-helix genes translocated in lymphoid leukemia. , 1991, Trends in biochemical sciences.

[17]  M. Bucan,et al.  Close genetic and physical linkage between the murine haemopoietic growth factor genes GM‐CSF and Multi‐CSF (IL3). , 1987, The EMBO journal.

[18]  Nic Jones,et al.  Transcriptional regulation by dimerization: Two sides to an incestuous relationship , 1990, Cell.

[19]  P. Sassone-Corsi,et al.  Developmental switch of CREM function during spermatogenesis: from antagonist to activator , 1992, Nature.

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

[21]  I. Verma,et al.  An alternative spliced form of FosB is a negative regulator of transcriptional activation and transformation by Fos proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  David Baltimore,et al.  A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins , 1989, Cell.

[23]  B. Lewin.  Oncogenic conversion by regulatory changes in transcription factors , 1991, Cell.

[24]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[25]  D. Gerhard,et al.  Isolation of the human insulin-like growth factor genes: insulin-like growth factor II and insulin genes are contiguous. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[26]  A. Feinberg,et al.  A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. , 1983, Analytical biochemistry.

[27]  H. Weintraub,et al.  Sequence-specific DNA binding by the c-Myc protein. , 1990, Science.

[28]  Iqbal Unnisa Ali,et al.  Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia , 1987 .

[29]  A. Look,et al.  Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes , 1988, Cell.

[30]  C. Rogler,et al.  Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas. , 1988, Cytogenetics and cell genetics.

[31]  A. Geiser,et al.  Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. , 1987, Science.

[32]  L. Su,et al.  TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. , 1990, Genes & development.

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

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

[35]  R. Tjian,et al.  Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. , 1990, Genes & development.

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

[37]  A. Feinberg,et al.  Loss of genes on the short arm of chromosome 11 in bladder cancer , 1985, Nature.

[38]  P. S. Kim,et al.  X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil. , 1991, Science.

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

[40]  S. McKnight,et al.  Scissors-grip model for DNA recognition by a family of leucine zipper proteins. , 1989, Science.

[41]  B. Wasylyk,et al.  Transformation suppressor activity of a Jun transcription factor lacking its activation domain , 1991, Nature.

[42]  E. Southern,et al.  Removal of repeated sequences from hybridisation probes. , 1985, Nucleic acids research.

[43]  N. Copeland,et al.  Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism , 1985, Nature.

[44]  James R. Woodgett,et al.  Phosphorylation of c-jun mediated by MAP kinases , 1991, Nature.

[45]  T. Kadesch,et al.  The leucine zipper of TFE3 dictates helix-loop-helix dimerization specificity. , 1991, Genes & development.