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Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties

Oncogene volume 20, pages 7051–7063 (2001)Cite this article

Abstract

Abnormalities in cellular differentiation are frequent occurrences in human cancers. Treatment of human melanoma cells with recombinant fibroblast interferon (IFN-β) and the protein kinase C activator mezerein (MEZ) results in an irreversible loss in growth potential, suppression of tumorigenic properties and induction of terminal cell differentiation. Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7), as a gene induced during these physiological changes in human melanoma cells. Ectopic expression of mda-7 by means of a replication defective adenovirus results in growth suppression and induction of apoptosis in a broad spectrum of additional cancers, including melanoma, glioblastoma multiforme, osteosarcoma and carcinomas of the breast, cervix, colon, lung, nasopharynx and prostate. In contrast, no apparent harmful effects occur when mda-7 is expressed in normal epithelial or fibroblast cells. Human clones of mda-7 were isolated and its organization resolved in terms of intron/exon structure and chromosomal localization. Hu-mda-7 encompasses seven exons and six introns and encodes a protein with a predicted size of 23.8 kDa, consisting of 206 amino acids. Hu-mda-7 mRNA is stably expressed in the thymus, spleen and peripheral blood leukocytes. De novo mda-7 mRNA expression is also detected in human melanocytes and expression is inducible in cells of melanocyte/melanoma lineage and in certain normal and cancer cell types following treatment with a combination of IFN-β plus MEZ. Mda-7 expression is also induced during megakaryocyte differentiation induced in human hematopoietic cells by treatment with TPA (12-O-tetradecanoyl phorbol-13-acetate). In contrast, de novo expression of mda-7 is not detected nor is it inducible by IFN-β+MEZ in a spectrum of additional normal and cancer cells. No correlation was observed between induction of mda-7 mRNA expression and growth suppression following treatment with IFN-β+MEZ and induction of endogenous mda-7 mRNA by combination treatment did not result in significant intracellular MDA-7 protein. Radiation hybrid mapping assigned the mda-7 gene to human chromosome 1q, at 1q 32.2 to 1q41, an area containing a cluster of genes associated with the IL-10 family of cytokines. Mda-7 represents a differentiation, growth and apoptosis associated gene with potential utility for the gene-based therapy of diverse human cancers.

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Acknowledgements

This study was supported in part by National Institutes of Health grant CA35675, CA80826, Columbia Skin Diseases Research Center (P30-AR44535), the Samuel Waxman Cancer Research Foundation, the Chernow Endowment and Introgen Therapeutics, Inc. MT Madireddi was supported by a fellowship award from the Army Department of Defense Initiative on Breast Cancer (DAMD17-98-1-8053). PB Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist in the Departments of Neurosurgery, Pathology and Urology. We thank Drs Theresa Druck and Kay Hubner for assistance with the chromosomal mapping of mda-7.

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Author notes

  1. Malavi T Madireddi

    Present address: Bristol Myers-Squibb, Age-related Diseases, MCDD 311, Pennington-Rocky Hill Road, Pennington, NJ 08534, USA

  2. Eric Y Huang, Malavi T Madireddi, Rahul V Gopalkrishnan, Magdalena Leszczyniecka, Zao-zhong Su and Irina V Lebedeva: EY Huang, MT Madireddi, RV Gopalkrishnan, M Leszczyniecka, Z-z Su and IV Lebedeva contributed equally to this manuscript

Authors and Affiliations

  1. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA

    Eric Y Huang, Malavi T Madireddi, Rahul V Gopalkrishnan, Magdalena Leszczyniecka, Zao-zhong Su, Irina V Lebedeva, Dong-chul Kang, Hongping Jiang, Jiao Jiao Lin, Deborah Alexandre, Yinming Chen, Nicollaq Vozhilla, Mei Xin Mei, Keith A Christiansen, Frank Sivo, Neil I Goldstein & Paul B Fisher

  2. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA

    Jiao Jiao Lin, Deborah Alexandre, Mei Xin Mei, Keith A Christiansen & Paul B Fisher

  3. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA

    Paul B Fisher

  4. Introgen Therapeutics Incorporated, Houston, Tx 77030, Texas, USA

    Abner B Mhashilkar & Sunil Chada

  5. Center for Mechanistic Biology and Biotechnology, Argonne National Laboratories, Argonne, IL 60439, Illinois, USA

    Eliezer Huberman

  6. Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854, New Jersey, USA

    Sidney Pestka

  7. DGI Biotechnologies Incorporated, Molecular Biology, 40 Talmadge Road, Edison, NJ 08818, USA

    Neil I Goldstein

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Correspondence to Paul B Fisher.

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Huang, E., Madireddi, M., Gopalkrishnan, R. et al. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 20, 7051–7063 (2001). https://doi.org/10.1038/sj.onc.1204897

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