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Mmip-2, a novel RING finger protein that interacts with mad members of the Myc oncoprotein network

Oncogene volume 18, pages 6621–6634 (1999)Cite this article

Abstract

Mad proteins are basic – helix – loop – helix – leucine zipper (bHLH-ZIP)-containing members of the myc oncoprotein network. They interact with the bHLH-ZIP protein max, compete for the same DNA binding sites as myc-max heterodimers and down-regulate myc-responsive genes. Using the bHLH-ZIP domain of mad1 as a yeast two-hybrid `bait', we identified Mmip-2, a novel RING finger protein that interacts with all mad members, but weakly or not at all with c-myc, max or unrelated bHLH or bZIP proteins. The mad1-Mmip-2 interaction is mediated by the ZIP domain in the former protein and by at least two regions in the latter which do not include the RING finger. Mmip-2 can disrupt max-mad DNA binding and can reverse the suppressive effects of mad proteins on c-myc-responsive target genes and on c-myc+ras-mediated focus formation in fibroblasts. Tagging with spectral variants of green fluorescent protein showed that Mmip-2 and mad proteins reside in separate cytoplasmic and nuclear compartments, respectively. When co-expressed, however, the proteins interact and translocate to the cellular compartment occupied by the more abundant protein. These observations suggest a novel way by which Mmip-2 can modulate the transcriptional activity of myc oncoproteins.

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Acknowledgements

We thank Simon Watkins for advice on epifluorescence microscopy and for help in preparing Figure 9, Linette Grove for DNA sequencing, and members of the Prochownik lab for comments on the manuscript. This work was supported by NIH grants HL33741 to EV Prochownik and NS32385 to ES Levitan.

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Authors and Affiliations

  1. Section of Hematology/Oncology, Children's Hospital of Pittsburgh, The University of Pittsburgh Cancer Institute, Pittsburgh, 15213, Pennsylvania, PA, USA

    Xiao-Ying Yin, Kalpana Gupta & Edward V Prochownik

  2. The Department of Molecular Genetics & Biochemistry, The University of Pittsburgh Cancer Institute, Pittsburgh, 15213, Pennsylvania, PA, USA

    Edward V Prochownik

  3. The Department of Pharmacology, The University of Pittsburgh Medical Center, The University of Pittsburgh Cancer Institute, Pittsburgh, 15213, Pennsylvania, PA, USA

    Wei Ping Han & Edwin S Levitan

  4. The University of Pittsburgh Cancer Institute, Pittsburgh, 15213, Pennsylvania, PA, USA

    Edward V Prochownik

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Yin, XY., Gupta, K., Han, W. et al. Mmip-2, a novel RING finger protein that interacts with mad members of the Myc oncoprotein network. Oncogene 18, 6621–6634 (1999). https://doi.org/10.1038/sj.onc.1203097

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