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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 Huang EY; Madireddi MT; Gopalkrishnan RV; Leszczyniecka M; Su Z; Lebedeva IV; Kang D; Jiang H; Lin JJ; Alexandre D; Chen Y; Vozhilla N; Mei MX; Christiansen KA; Sivo F; Goldstein NI; Mhashilkar AB; Chada S; Huberman E; Pestka S; Fisher PBOncogene 2001[Oct]; 20 (48): 7051-63Abnormalities in cellular differentiation are frequent occurrences in human cancers. Treatment of human melanoma cells with recombinant fibroblast interferon (IFN-beta) 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-beta 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-beta+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-beta+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.|*Diterpenes[MESH]|*Genes[MESH]|*Interleukins[MESH]|Antigens, Neoplasm/biosynthesis/*genetics/isolation & purification[MESH]|Apoptosis/*genetics[MESH]|Base Sequence[MESH]|Carcinoma/pathology[MESH]|Cell Differentiation/drug effects/genetics[MESH]|Cell Division/genetics[MESH]|Chromosomes, Human, Pair 1/*genetics[MESH]|Cloning, Molecular[MESH]|Dimethyl Sulfoxide/pharmacology[MESH]|Female[MESH]|Gene Expression Regulation, Neoplastic/drug effects[MESH]|Genes, Tumor Suppressor[MESH]|Glioblastoma/pathology[MESH]|Growth Substances/biosynthesis/*genetics/isolation & purification[MESH]|HL-60 Cells/metabolism/pathology[MESH]|Humans[MESH]|Interferon Type I/pharmacology[MESH]|K562 Cells/metabolism/pathology[MESH]|Male[MESH]|Melanocytes/metabolism[MESH]|Melanoma/chemistry/genetics/pathology[MESH]|Molecular Sequence Data[MESH]|Molecular Weight[MESH]|Neoplasm Proteins/biosynthesis/*genetics/isolation & purification[MESH]|Neoplasms/*genetics[MESH]|Organ Specificity[MESH]|Osteosarcoma/pathology[MESH]|RNA, Messenger/biosynthesis/genetics[MESH]|RNA, Neoplasm/biosynthesis/genetics[MESH]|Recombinant Fusion Proteins/physiology[MESH]|Recombinant Proteins[MESH]|Terpenes/pharmacology[MESH]|Tetradecanoylphorbol Acetate/pharmacology[MESH]|Transfection[MESH]|Tumor Cells, Cultured/pathology[MESH] |
