Regulation of mda-7 gene expression during human melanoma differentiation

Madireddi, Malavi T.; Dent, Paul; Fisher, Paul B.

doi:10.1038/sj.onc.1203424

Cited by 50 publications

(60 citation statements)

References 35 publications

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“…Delay of mRNA degradation is a common posttranscriptional mechanism to up-regulate the expression of these proteins. The half-life of mda-7/IL-24 mRNA in unstimulated cells is Ͻ20min, well in line with data reported earlier in other cells (34,35). The instability is conferred by ARE located in the 3Ј-UTR (35).…”

Section: Discussionsupporting

confidence: 78%

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Sauane¹,

Gupta³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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A noteworthy aspect of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) as a cancer therapeutic is its ability to selectively kill cancer cells without harming normal cells. Intracellular MDA-7/IL-24 protein, generated from an adenovirus expressing mda-7/IL-24 (Ad.mda-7), induces cancerspecific apoptosis by inducing an endoplasmic reticulum (ER) stress response. Secreted MDA-7/IL-24 protein, generated from cells infected with Ad.mda-7, induces growth inhibition and apoptosis in surrounding noninfected cancer cells but not in normal cells, thus exerting an anti-tumor ''bystander'' effect. The present studies reveal a provocative finding that recombinant MDA-7/IL-24 protein can robustly induce expression of endogenous mda-7/IL-24, which generates the signaling events necessary for bystander killing. To evaluate the mechanism underlying this positive autocrine feedback loop, we show that MDA-7/IL-24 protein induces stabilization of its own mRNA without activating its promoter. Furthermore, this posttranscriptional effect depends on de novo protein synthesis. As a consequence of this autocrine feedback loop MDA-7/IL-24 protein induces sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, GADD153, and phosphoeIF2␣) and reactive oxygen species production, indicating that both intracellular and secreted proteins activate similar signaling pathways to induce apoptosis. Thus, our results clarify the molecular mechanism by which secreted MDA-7/IL-24 protein (generated from Ad.mda-7-infected cells) exerts cancer-specific killing.bystander antitumor activity ͉ endoplasmic reticulum stress ͉ reactive oxygen species ͉ mRNA stabalization ͉ cancer-specific killing

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Section: Discussionsupporting

confidence: 78%

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Sauane¹,

Gupta³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

117

153

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“…Using the two methods described above a contiguous mda-7 genomic sequence was obtained. The mda-7 transcription unit is 6.33 Kbp, subsequent DNA walking resulted in the cloning of an additional 2.2 Kbp of the 5'-¯anking region which contains the mda-7 promoter (Madireddi et al, 2000a). The nucleotide sequence of human mda-7 and exon/ intron boundaries are shown in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…Analyses of the 5'-upstream nucleotide sequence reveals the presence of a TATA element at position 730 to 725 (Figure 1). Elimination of this TATA element resulted in a complete loss in promoter activity (Madireddi et al, 2000a).…”

Section: Resultsmentioning

confidence: 99%

“…At least a partial answer comes from previous studies in melanoma cells which suggest that the mda-7 promoter is constitutively active in melanoma cells, whereas mda-7 mRNA expression is restricted to melanoma cells treated with IFN-b+MEZ and induced to terminally di erentiate (Madireddi et al, 2000a,b). These ®ndings suggest that post-transcriptional modi®cations may contribute to mda-7 mRNA levels in human melanoma cells (Madireddi et al, 2000a). To address the question of cell context speci®c expression of mda-7 we have evaluated the e ect of IFN-b+MEZ on mda-7 mRNA expression in a panel of normal and cancer cell types (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, mda-7 mRNA levels during terminal di erentiation are partly regulated by di erential post-transcriptional-message stabilization dictated by the AU-rich (ARE) sequences present in the 3'-untranslated region of the mda-7 cDNA (Madireddi et al, 2000a). To further characterize this cancer suppressor gene we have isolated mda-7 genomic DNA from human cells and de®ned its gene structure and analysed endogenous and inducible expression in melanocyte/melanoma and other lineage cells.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2001

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Abnormalities in cellular di erentiation are frequent occurrences in human cancers. Treatment of human melanoma cells with recombinant ®broblast interferon (IFN-b) 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 di erentiation. Subtraction hybridization identi®ed melanoma di erentiation 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 e ects occur when mda-7 is expressed in normal epithelial or ®broblast cells. Human clones of mda-7 were isolated and its organization resolved in terms of intron/exon structure and chromosomal localization. Humda-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-b plus MEZ. Mda-7 expression is also induced during megakaryocyte di erentiation 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-b+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-b+MEZ and induction of endogenous mda-7 mRNA by combination treatment did not result in signi®cant 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 di erentiation, growth and apoptosis associated gene with potential utility for the gene-based therapy of diverse human cancers. Oncogene (2001) 20, 7051 ± 7063.

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AP-1 and C/EBP transcription factors contribute tomda-7 gene promoter activity during human melanoma differentiation

2000

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Treatment of human melanoma cells with a combination of recombinant fibroblast interferon (IFN-beta) and the protein kinase C (PKC) activator mezerein (MEZ) causes a rapid and irreversible suppression in growth and terminal cell differentiation. Temporal subtraction hybridization combined with random clone selection, reverse Northern hybridization, high throughput microchip cDNA array screening, and serial cDNA library arrays permit the identification and cloning of genes that are differentially expressed during proliferative arrest and terminal differentiation in human melanoma cells. A specific melanoma differentiation associated (mda) gene, mda-7, exhibits reduced expression as a function of melanoma progression from melanocyte to metastatic melanoma. In contrast, treatment of metastatic melanoma cells with IFN-beta + MEZ results in expression of mda-7 mRNA and protein. To evaluate the mechanism underlying the differential expression of mda-7 as a function of melanoma progression and induction of growth arrest and differentiation in human melanoma cells the promoter region of this gene has been isolated from a human placental genomic library and characterized. Sequence analysis by GCG identifies multiple recognition sites for the AP-1 and C/EBP transcription factors. Employing a heterologous mda-7 luciferase gene reporter system, we demonstrate that ectopic expression of either AP-1/cJun or C/EBP can significantly enhance expression of the mda-7 promoter in melanoma cells. In contrast, a dominant negative mutant of cJun, TAM67, is devoid of promoter-enhancing ability. Western blot analyses reveals that cJun and the C/EBP family member C/EBP-beta are physiologically relevant transcription factors whose expression corresponds with mda-7 mRNA expression. Electrophoretic mobility shift assays (EMSA) performed using nuclear protein extracts from terminally differentiated human melanoma cells document binding to regions of the mda-7 promoter that correspond to consensus binding sites for AP-1 and C/EBP. These results provide further mechanistic insights into the regulation of the mda-7 gene during induction of terminal cell differentiation in human melanoma cells.

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Regulation of mda-7 gene expression during human melanoma differentiation

Cited by 50 publications

References 35 publications

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

Autocrine regulation of mda -7/IL-24 mediates cancer-specific apoptosis

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

AP-1 and C/EBP transcription factors contribute tomda-7 gene promoter activity during human melanoma differentiation

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