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.
Abnormalities 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.
Huang
E Y
EY
Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Madireddi
M T
MT
Gopalkrishnan
R V
RV
Leszczyniecka
M
M
Su
Z
Z
Lebedeva
I V
IV
Kang
D
D
Jiang
H
H
Lin
J J
JJ
Alexandre
D
D
Chen
Y
Y
Vozhilla
N
N
Mei
M X
MX
Christiansen
K A
KA
Sivo
F
F
Goldstein
N I
NI
Mhashilkar
A B
AB
Chada
S
S
Huberman
E
E
Pestka
S
S
Fisher
P B
PB
D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002277:Carcinoma / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003001:Cloning, Molecular; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004224:Diterpenes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005796:Genes; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000473:pathology; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D018922:HL-60 Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007378:Interleukins; D020014:K562 Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D009369:Neoplasms / Q000235:genetics*; D009928:Organ Specificity; D012516:Osteosarcoma / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000473:pathology; D000099180:Interleukin-24
D000951:Antigens, Neoplasm; D004121:Dimethyl Sulfoxide; D004224:Diterpenes; D006133:Growth Substances; D007370:Interferon Type I; D007378:Interleukins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013729:Terpenes; D013755:Tetradecanoylphorbol Acetate; D000099180:Interleukin-24; C011309:mezerein