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Query: HUMANGGP:010955 (
mda-7
)
464
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cultured human melanoma cells lose proliferative capacity and terminally differentiate after treatment with the combination of recombinant human fibroblast
interferon
(IFN-beta) and mezerein (MEZ). Subtraction hybridization of cDNA libraries prepared from actively proliferating human H0-1 melanoma cells from cDNA libraries produced from H0-1 cells treated with IFN-beta + MEZ identifies a novel melanoma differentiation-associated (mda) cDNA,
mda-7
, that displays elevated expression in differentiation inducer-treated H0-1 cells.
mda-7
encodes a novel protein of 206 amino acids with a predicted size of 23.8 kDa. The level of
mda-7
mRNA is elevated in actively proliferating normal human melanocytes versus primary and metastatic human melanomas. In the Matrigel-assisted melanoma progression model,
mda-7
expression decreases in early vertical growth phase primary human melanoma cells selected for autonomous or enhanced tumor formation in nude mice. Treatment of human melanomas with IFN-beta + MEZ, and to a lesser extent with MEZ, results in growth suppression and induced or enhanced
mda-7
expression. Immunoprecipitation analyses using peptide-derived rabbit polyclonal antibodies detect increases in
mda-7
protein, and a higher molecular weight protein of approximately 90 to 100 kDa, in MEZ and IFN-beta + MEZ treated H0-1 cells.
mda-7
is a highly conserved gene with an homologous sequence in the genome of yeast. Transfection of
mda-7
expression constructs into H0-1 and C8161 human melanoma cells reduces growth and inhibits colony formation. These results confirm that
mda-7
has antiproliferative properties in human melanoma cells and in this context may contribute to terminal cell differentiation. The
mda-7
gene may also function as a negative regulator of melanoma progression.
...
PMID:Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. 854 4
Cancer is a disease characterized by defects in growth control, and tumor cells often display abnormal patterns of cellular differentiation. The combination of recombinant human fibroblast
interferon
and the antileukemic agent mezerein corrects these abnormalities in cultured human melanoma cells resulting in irreversible growth arrest and terminal differentiation. Subtraction hybridization identifies a melanoma differentiation associated gene (
mda-7
) with elevated expression in growth arrested and terminally differentiated human melanoma cells. Colony formation decreases when
mda-7
is transfected into human tumor cells of diverse origin and with multiple genetic defects. In contrast, the effects of
mda-7
on growth and colony formation in transient transfection assays with normal cells, including human mammary epithelial, human skin fibroblast, and rat embryo fibroblast, is quantitatively less than that found with cancer cells. Tumor cells expressing elevated
mda-7
display suppression in monolayer growth and anchorage independence. Infection with a recombinant type 5 adenovirus expressing antisense
mda-7
eliminates
mda-7
suppression of the in vitro growth and transformed phenotype. The ability of
mda-7
to suppress growth in cancer cells not expressing or containing defects in both the retinoblastoma (RB) and p53 genes indicates a lack of involvement of these critical tumor suppressor elements in mediating
mda-7
-induced growth inhibition. The lack of protein homology of
mda-7
with previously described growth suppressing genes and the differential effect of this gene on normal versus cancer cells suggests that
mda-7
may represent a new class of cancer growth suppressing genes with antitumor activity.
...
PMID:The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. 879 71
Induction of irreversible growth arrest and terminal differentiation in human melanoma cells following treatment with recombinant human fibroblast
interferon
(IFN-beta) and mezerein (MEZ) results in elevated expression of a specific melanoma differentiation associated gene,
mda-7
. Experiments were conducted to define the mechanism involved in the regulation of
mda-7
expression in differentiating human melanoma cells. The
mda-7
gene is actively transcribed in uninduced HO-1 human melanoma cells and the rate of transcription of
mda-7
is not significantly enhanced by treatment with IFN-beta, MEZ or IFN-beta+MEZ. The high basal activity of the
mda-7
promoter in uninduced melanoma cells and the absence of enhancing effect upon treatment with differentiation inducers is corroborated by transfection studies using the promoter region of
mda-7
linked to a luciferase reporter gene containing the SV40 polyadenylation signal sequence. RT - PCR analysis detects the presence of low levels of
mda-7
transcripts in uninduced and concomitant increases in differentiation inducer treated HO-1 cells. However, steady-state
mda-7
mRNA is detected only in IFN-beta+MEZ and to a lesser degree in MEZ treated cells. We show that induction of terminal differentiation of HO-1 cells with IFN-beta+MEZ dramatically increases the half-life of
mda-7
mRNA while treatment with cycloheximide results in detectable
mda-7
mRNA in control and inducer treated cells. These observations confirm constitutive activity of the
mda-7
promoter in HO-1 cells irrespective of differentiation status suggesting posttranscriptional processes as important determinants of
mda-7
expression during terminal differentiation. The 3' UTR region of
mda-7
contains AU-rich elements (ARE) that contribute to rapid
mda-7
mRNA turnover during proliferation and reversible differentiation, a process controlled by a labile protein factor(s). Substitution of the SV40 polyadenylation signal sequence in the luciferase reporter plasmid with the
mda-7
-ARE-3'-UTR renders the Luciferase message unstable when expressed in proliferating and reversibly differentiated melanoma cells. In contrast, the luciferase message is stabilized when the
mda-7
-ARE-3'-UTR construct is expressed in terminally differentiated HO-1 cells. These results provide compelling evidence that
mda-7
expression during terminal differentiation in human melanoma cells is regulated predominantly at a posttranscriptional level.
...
PMID:Regulation of mda-7 gene expression during human melanoma differentiation. 1071 78
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.
...
PMID:AP-1 and C/EBP transcription factors contribute to mda-7 gene promoter activity during human melanoma differentiation. 1094 17
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.
...
PMID: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. 1170 29
Human melanoma cells growth arrest irreversibly, lose tumorigenic potential and terminally differentiate after treatment with a combination of fibroblast
interferon
(IFN-beta) and the protein kinase C activator mezerein (MEZ). Applying subtraction hybridization to this model differentiation system permitted cloning of melanoma differentiation associated gene-7,
mda-7
. Expression of
mda-7
inversely correlates with melanoma development and progression, with elevated expression in normal melanocytes and nevi and increasingly reduced expression in radial growth phase, vertical growth phase and metastatic melanoma. When expressed by means of a replication incompetent adenovirus (Ad.
mda-7
) growth of melanoma, but not normal early passage or immortal human melanocytes, is dramatically suppressed and cells undergo programmed cell death (apoptosis). Infection of metastatic melanoma cells with Ad.
mda-7
results in an increase in cells in the G(2)/M phase of the cell cycle and changes in the ratio of pro-apoptotic (BAX, BAK) to anti-apoptotic (BCL-2, BCL-XL) proteins. Ad.
mda-7
infection results in a temporal increase in
mda-7
mRNA and intracellular
MDA-7
protein in most of the melanocyte/melanoma cell lines and secretion of
MDA-7
protein is readily detected following Ad.
mda-7
infection of both melanocytes and melanoma cells. The present studies document a differential response of melanocytes versus melanoma cells to ectopic expression of
mda-7
and support future applications of
mda-7
for the gene-based therapy of metastatic melanoma.
...
PMID:The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. 1185 Jul 99
The is a double-stranded RNA-activated protein kinase (PKR) has been largely investigated for its key role in viral host defense. Although best characterized by its function in mediating the antiviral and antiproliferative effects of
interferon
(
IFN
), PKR is also implicated in transcriptional regulation, cell differentiation, signal transduction, and tumor suppression. However, recent findings identifying PKR as an important effector of apoptosis have led to an increased interest in PKR modulation as an antitumor strategy. PKR can either be up-regulated through direct induction by the transcription factor E2F-1, or it can be activated through direct protein-protein interactions with the melanoma differentiation-associated gene-7 (
MDA7
, IL-24). Additionally, the intracellular formation of double-stranded RNA by transfection with antisense RNA complementary to tumor-specific RNA sequences can induce PKR activation and apoptosis selective to these tumor cells. The growing application of viral vector-based gene therapies and oncolytic, replicating viruses that must elude viral defense in order to be effective, has also drawn attention to PKR. Oncolytic viruses, like the attenuated herpes simplex virus R3616, the vesicular stomatitis virus, or reovirus, specifically replicate in tumor cells only because the viral host defense in the permissive cells is suppressed. In this article we review the role of PKR as an effector of apoptosis and a target for tumor treatment strategies and discuss the potential of PKR-modifying agents to treat patients with cancer. Targeted gene therapy against cancer can be approached by activation of PKR with the down-regulation of protein synthesis and induction of apoptosis, or by suppression of PKR with the propagation of oncolytic virus. Since the PKR pathway can be modified by many routes, antitumor therapies combining oncolytic virus, gene therapies, and chemotherapy with PKR modifiers are likely to emerge in the near future as therapeutic options in the treatment of patients with cancer.
...
PMID:Genetically targeted cancer therapy: tumor destruction by PKR activation. 1517
Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). The cDNA-oligoarray analysis and reverse transcription-PCR verification indicated common changes in gene expression in methionine-dependent cell lines to include up-regulation/induction of cyclin D1, mitotic arrest deficient (MAD)1, p21, growth arrest and DNA-damage-inducible (GADD)45 alpha, GADD45 gamma, GADD34, breast cancer (BRCA)1, 14-3-3sigma, B-cell CLL/lymphoma (BCL)1, transforming growth factor (TGF)-beta, TGF-beta-induced early response (TIEG), SMAD5, SMAD7, SMAD2, insulin-like growth factor binding protein (IGFBP7), IGF-R2, vascular endothelial growth factor (VEGF), TNF-related apoptosis-inducing ligand (TRAIL), TNF-alpha converting enzyme (TACE), TRAIL receptor (TRAIL-R)2, TNFR-related death receptor (DR)6, TRAF interacting protein (I-TRAF), IL-6,
MDA7
, IL-1B convertase (ICE)-gamma, delta and epsilon, IRF1, IRF5, IRF7,
interferon
(
IFN
)-gamma and receptor components, ISG15, p65-NF-kappaB, JUN-B, positive cofactor (PC)4, C/ERB-beta, inositol triphosphate receptor I, and methionine adenosyltransferase II. On the other hand, cyclins A1, A2, B1 and B2, cell division cycle (CDC)2 and its kinase, CDC25 A and B, budding uninhibited by benzimidazoles (BUB)1 and 3, MAD2, CDC28 protein kinase (CKS)1 and 2, neuroepithelial cell transforming gene (NET)1, activator of S-phase kinase (ASK), CDC14B phosphatase, BCL2, TGF-beta activated kinase (TAK)1, TAB1, c-FOS, DNA topoisomerase II, DNA polymerase alpha, dihydrofolate reductase, thymidine kinase, stathmin, and MAP4 were down-regulated. In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45alpha and gamma in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of
MDA7
and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress down-regulated the highly active phosphatidylinositol 3'-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor kappaB under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.
...
PMID:Modulation of gene expression in human central nervous system tumors under methionine deprivation-induced stress. 1549 78
"Differentiation therapy" provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining "differentiation therapy" with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast
interferon
(IFN-beta) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene,
mda-7
, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (
mda-7
/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells.
mda-7
/IL-24 displays potent "bystander antitumor" activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered
mda-7
/IL-24 (Ad.
mda-7
) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.
...
PMID:mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. 1646 4
Restoration of the tumor-suppression function by gene transfer of the melanoma differentiation-associated gene 7 (MDA7)/
interleukin 24
(
IL-24
) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/
IL-24
treatment of melanoma cells down-regulates
interferon
regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1-regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN-alpha) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN (IFN-gamma), on the other hand, supports melanoma cell survival, possibly through constitutive activation of iNOS expression. We therefore conducted this study to explore the molecular pathways of MDA7/
IL-24
regulation of apoptosis via the intracellular induction of IFNs in melanoma. We hypothesized that the restoration of the MDA7/
IL-24
axis leads to upregulation of class I IFNs and induction of the apoptotic cascade. We found that MDA7/
IL-24
induces the secretion of endogenous IFN-beta, another class I IFN, leading to the arrest of melanoma cell growth and apoptosis. We also identified a series of apoptotic markers that play a role in this pathway, including the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-FasL. In summary, we described a novel pathway of MDA7/
IL-24
regulation of apoptosis in melanoma tumors via endogenous IFN-beta induction followed by IRF regulation and TRAIL/FasL system activation.
...
PMID:Killing of human melanoma cells induced by activation of class I interferon-regulated signaling pathways via MDA-7/IL-24. 1851 Dec 92
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