mel‐18, a Polycomb group‐related mammalian gene, encodes a transcriptional negative regulator with tumor suppressive activity.

The mammalian mel‐18/bmi‐1 gene products share an amino acid sequence and a secondary structure, including a RING‐finger motif, with the Drosophila Polycomb group (PcG) gene products Psc and Su(z)2, implying that they represent a gene family with related functions. As Drosophila PcG gene products are thought to function as transcriptional repressors by modifying chromatin structure, Mel‐18/Bmi‐1 might be expected to have similar activities. Here we have analyzed the function of mel‐18 and found that Mel‐18 acts as a transcriptional repressor via its target DNA sequence, 5′‐GACTNGACT‐3′. Interestingly, this binding sequence is found within regulatory or non‐coding regions of various genes, including the c‐myc, bcl‐2 and Hox genes, suggesting diverse functions of mel‐18 as the mammalian homolog of the PcG gene. We also demonstrate that mel‐18 has tumor suppressor activity, in contrast to bmi‐1, which has been defined as a proto‐oncogene.

[1]  Anton Berns,et al.  Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging , 1991, Cell.

[2]  David Housman,et al.  WT-1 is required for early kidney development , 1993, Cell.

[3]  C. Cordon-Cardo,et al.  Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. , 1993, Journal of the National Cancer Institute.

[4]  M. Frasch,et al.  Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2 , 1991, Nature.

[5]  M. Boguski,et al.  A novel RING finger protein interacts with the cytoplasmic domain of CD40. , 1994, The Journal of biological chemistry.

[6]  P. Gruss,et al.  The oncogenic potential of Pax genes. , 1993, The EMBO journal.

[7]  M. Yoshida,et al.  Cloning and chromosome mapping of the human Mel-18 gene which encodes a DNA-binding protein with a new 'RING-finger' motif. , 1993, Gene.

[8]  S. Rusconi,et al.  Transcriptional activation modulated by homopolymeric glutamine and proline stretches. , 1994, Science.

[9]  W. Alexander,et al.  Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in Eμ-myc transgenic mice , 1991, Cell.

[10]  T. Rabbitts,et al.  Chromosomal translocations in human cancer , 1994, Nature.

[11]  E. White,et al.  Death-defying acts: a meeting review on apoptosis. , 1993, Genes & development.

[12]  R. Paro,et al.  In vivo binding pattern of a trans-regulator of homoeotic genes in Drosophila melanogaster , 1989, Nature.

[13]  D. Green,et al.  Apoptotic cell death induced by c-myc is inhibited by bcl-2 , 1992, Nature.

[14]  G. Evan,et al.  Cooperative interaction between c-myc and bcl-2 proto-oncogenes , 1992, Nature.

[15]  P. Adler,et al.  Drosophila genes Posterior Sex Combs and Suppressor two of zeste encode proteins with homology to the murine bmi-1 oncogene , 1991, Nature.

[16]  A. Stein,et al.  Effects of plasmid length and positioned nucleosomes on chromatin assembly in vitro. , 1993, Biochemistry.

[17]  A. Stein,et al.  Chromatin assembly on plasmid DNA in vitro. Apparent spreading of nucleosome alignment from one region of pBR327 by histone H5. , 1991, Journal of molecular biology.

[18]  J. Trowsdale,et al.  A novel gysteine-rich sequence motif , 1991, Cell.

[19]  H. Matsubara,et al.  Expression of novel DNA-binding protein with zinc finger structure in various tumor cells. , 1990, The Journal of biological chemistry.

[20]  W. Gelbart,et al.  The Drosophila Polycomb-group gene Enhancer of zeste contains a region with sequence similarity to trithorax , 1993, Molecular and cellular biology.

[21]  John Calvin Reed,et al.  A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40 , 1995, FEBS letters.

[22]  S W Lin,et al.  Vectors for selective expression of cloned DNAs by T7 RNA polymerase. , 1987, Gene.

[23]  H. Weintraub,et al.  Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection. , 1990, Science.

[24]  D. Goeddel,et al.  A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor , 1994, Cell.

[25]  Prim B. Singh,et al.  The mouse has a Polycomb-like chromobox gene. , 1992, Development.

[26]  Renato Paro,et al.  Mapping polycomb-repressed domains in the bithorax complex using in vivo formaldehyde cross-linked chromatin , 1993, Cell.

[27]  T. Taniguchi,et al.  Reconstitution of functional receptor for human interleukin-2 in mouse cells , 1985, Nature.

[28]  H. Waterham,et al.  The Hansenula polymorpha PER8 gene encodes a novel peroxisomal integral membrane protein involved in proliferation , 1995, The Journal of cell biology.

[29]  S. Green,et al.  A versatile in vivo and in vitro eukaryotic expression vector for protein engineering , 1988, Nucleic Acids Res..

[30]  M. Sofroniew,et al.  Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. , 1994, Genes & development.

[31]  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.