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At least 217 records · Page 12Linked to original sources
PubMed1989

Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats.

1. Chondrocyte activities within growth plate cartilage are the principal determinants of longitudinal bone growth, and it was the aim of this investigation to assess how these cell activities are modulated under various growth rate conditions. Using proximal tibial growth plates from rats of different ages, growth rate was determined by fluorochrome labelling and incident light fluorescence microscopy. Various cellular parameters contributing to longitudinal bone growth were quantified by light microscopic stereology. The size of the proliferating cell population ('growth fraction') was estimated by autoradiography (using [3H]thymidine labelling). 2. A comparison between data for suckling (21-day-old) and fast-growing (35-day-old) rats revealed that growth acceleration is achieved almost exclusively by cell-shape modelling, namely by an increase in final cell height and a decrease in lateral diameter, whereas final cell volume and surface area are slightly reduced. Cell proliferation rate in the longitudinal direction and net matrix production per cell remain unchanged. The physiological increase in linear growth rate thus appears to be based principally upon a controlled structural modulation of the chondrocyte phenotype. On the other hand, a physiological reduction in growth rate (i.e. growth deceleration) effected during the transition from pre-puberty (35-day-old rats) to maturity (80-day-old rats) is achieved by simultaneous decreases in several chondrocyte parameters, including cell height (i.e. phenotype modulation), cell volume and proliferation rate (in the longitudinal direction). However, chondrocytes continue to produce matrix at a level comparable to that attained during the period characterized by high growth rates (i.e. at 21 and 35 days). Cartilage matrix thus appears to play a subordinate role in regulating longitudinal bone growth rate. The duration of the hypertrophic cell activity (i.e. phenotype modulation) phase remains constant (at approximately 2 days) under the various growth rate conditions. 3. The findings presented in this study indicate that measurement of bulk parameters such as [35S]sulphate incorporation into matrix components, [3H]thymidine uptake by cells and growth plate height are of limited value as estimators of longitudinal bone growth, since changes in the parameters that these measurements quantify bear little relationship to changes in linear growth rate, and may be useful only as indicators of total growth plate activity.

Aging↗
PubMed1999

Activation of mitogen-activated protein kinase pathways by cyclic GMP and cyclic GMP-dependent protein kinase in contractile vascular smooth muscle cells.

Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo. The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic GMP (cGMP) signaling, the cGMP-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cGMP activated extracellular signal- regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cGMP on ERK and JNK activation were also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cGMP signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cGMP and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2005

Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder.

Mitochondrial DNA (mtDNA) mutations are a major cause of human disease. A large number of different molecular defects ultimately compromise oxidative phosphorylation, but it is not clear why the same biochemical defect can cause diverse clinical phenotypes. There is emerging evidence that nuclear genes modulate the phenotype of primary mtDNA disorders. Here, we define an X-chromosomal haplotype that interacts with specific MTND mutations to cause visual failure in the most common mtDNA disease, Leber hereditary optic neuropathy. This effect is independent of the mtDNA genetic background and explains the variable penetrance and sex bias that characterizes this disorder.

Alleles↗
PubMed2001

IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway.

BACKGROUND: Myofibroblasts play a role in the airway remodeling response of bronchial asthma. IL-4 and IL-13 are possibly involved in the airway remodeling response by inducing extracellular matrix production by fibroblasts. However, the roles of these cytokines in inducing the phenotypic modulation of human lung fibroblasts (HLFs) to myofibroblasts and the intracellular signal have not been determined. OBJECTIVE: We examined the effect of IL-4 and IL-13 on inducing the phenotypic modulation of HLFs to myofibroblasts characterized by alpha-smooth muscle actin and examined the role of the mitogen-activated protein (MAP) kinase superfamily in inducing the myofibroblastic phenotype of the HLF to clarify these issues. METHODS: Phosphorylation and activities of c-Jun NH(2)-terminal kinase (JNK), p38 MAP kinase, and extracellular signal-regulated kinase (Erk) were examined by using Western blotting and in vitro kinase assay. Expression of alpha-smooth muscle actin in IL-4- and IL-13-stimulated HLFs was analyzed by means of Western blotting. RESULTS: The results showed that (1) IL-4 and IL-13 increased alpha-smooth muscle actin expression in a dose- and time-dependent manner; (2) IL-4 and IL-13 induced increases in JNK and Erk phosphorylation and activity but not p38 MAP kinase activity; (3) CEP-1347 and PD 98059 attenuated IL-4- and IL13-induced JNK and Erk activity, respectively; and (4) CEP-1347, but not PD 98059, attenuated IL-4- and IL-13-induced alpha-smooth muscle actin expression. CONCLUSION: These results indicate that IL-4 and IL-13 are capable of inducing the phenotypic modulation of HLFs to myofibroblasts, and JNK, but not p38 MAP kinase and Erk, regulates IL-4- and IL-13-induced phenotypic modulation of HLFs to myofibroblasts.

Actins↗
PubMedDate not supplied

Enhanced embryonic nonmuscle myosin heavy chain isoform and matrix metalloproteinase expression in aortic abdominal aneurysm with rapid progression.

Abdominal aortic aneurysms (AAAs) are characterized by structural deterioration of aortic wall leading to progressive dilatation. The histopathological changes in AAAs are particularly evident within the elastic media, which is normally comprised mainly of vascular smooth muscle cells (SMCs). There are vascular myosin heavy chain (MHC) isoforms; SM2 is specifically expressed in differentiated SMCs and SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of the fetal aorta with an immature phenotype. Although AAA altered expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), pathophysiological role of SMC phenotypic modulation in the AAA progression remains uncertain. To determine whether phenotypic modulation in vascular SMCs contributes to arterial medial degeneration, we examined MHC expression in SMCs of AAA. Aortic specimens were obtained from patients with slowly progressed AAA (n = 12) and rapidly progressed AAA (n = 5), and compared with normal aortic tissue (n = 3). Immunohistochemical staining was performed for detection of SMemb, SM2, MMP (types 2 and 9) and TIMP (types 1 and 2). Faint SMemb and abundant SM2 were observed in normal aorta, while the balance shifted to SMemb predominance in AAAs. Compared with slowly progressed AAA tissue, rapidly expanded AAA tissue demonstrated marked increases in SMemb expression with suppressed SM2. Predominant SMemb expression indicates presence of phenotypic modulated SMCs and enhanced MMP; while abundant TIMP was seen in mature SMCs expressing SM2. SMemb expression is markedly increased in AAA with MMP enhancement, and a significant imbalance between SMemb and SM2 results in rapid progression of AAA.

Aged↗
PubMed1998

Effect of estrogen on vascular smooth muscle cells is dependent upon cellular phenotype.

To investigate the growth-regulating action of estrogen on vascular smooth muscle cells (SMC), effects of beta-17-estradiol (beta-E2) on phenotypic modulation and proliferation of rabbit aortic SMC were observed in vitro. At 10(-8)M, beta-E2 significantly slowed the decrease in volume fraction of myofilaments (Vv myo) of freshly dispersed SMCs in primary culture, indicating an inhibitory effect of beta-E2 on spontaneous phenotypic modulation of SMC from a contractile to a synthetic phenotype. Freshly dispersed SMCs treated with beta-E2 also had a relatively longer quiescent phase than control cells before intense proliferation occurred. This was in contrast to SMCs in passage 2 3 (synthetic state), where beta-E2-treated cells replicated significantly faster than untreated cells. beta-E2 also markedly enhanced the serum-induced DNA synthesis of synthetic SMCs in a concentration-dependent manner within physiological range (10(-10)to 10(-8)M). These findings indicate that the growth-regulating effect of estrogen on vascular SMC is dependent on the cell's phenotypic state. It delays the cell cycle re-entry of the contractile SMCs by retarding their phenotypic modulation: however, once cells have modulated to the synthetic phenotype, it promotes their replication.

Animals↗
PubMed1986

Modulation of the rabbit chondrocyte phenotype by retinoic acid terminates type II collagen synthesis without inducing type I collagen: the modulated phenotype differs from that produced by subculture.

The differentiated phenotype of rabbit articular chondrocytes can be characterized by the synthesis of high levels of cartilage specific proteoglycan and collagen (type II). Treatment of these cells in primary monolayer culture for periods of up to 18 days with 0.03 to 3.0 micrograms/ml retinoic acid (RA) resulted in suppression of colony formation, altered morphology, and decreased (eightfold) proteoglycan and collagen synthesis. With the exception of collagen synthesis, these changes were complete with all doses after 4 days of treatment. Collagen synthesis declined more slowly; it was dose dependent after 4 days and maximally inhibited by all doses by 9 days. Detailed analysis of the collagen phenotype was performed using SDS-PAGE of intact chains and 2-D CNBr peptide analysis. RA caused cessation of type II synthesis, and transient stimulation of type III and type I trimer collagen synthesis, without induction of type I collagen. Essentially identical results were obtained with retinol. The resultant collagen phenotype differed significantly from the type I-containing phenotype induced by subculture. Thus, suppression of this differentiated program did not elicit a common modulated phenotype. The results are discussed in the context of direct and indirect mechanisms of RA-dependent modulation of chondrocyte gene expression.

Animals↗
PubMed1992

Renal injury from angiotensin II-mediated hypertension.

Angiotensin II (Ang II)-mediated hypertension induces vascular smooth muscle cell hypertrophy and hyperplasia in systemic blood vessels, but the effects of Ang II on the intrinsic cell populations within the kidney have been less well characterized. We infused Ang II for 14 days into rats by minipump at doses (200 ng/min) that resulted in moderate hypertension (mean systolic blood pressure 156-172 mm Hg). Small renal arterial vessels of Ang II-infused rats demonstrated focal injury with fibrinoid necrosis and medial hyperplasia, whereas the glomerular capillaries demonstrated only rare segmental hyalinosis. Proliferation of vascular smooth muscle cells was pronounced (fourfold to 20-fold increase in [3H]thymidine incorporation) as opposed to a minimal proliferation of glomerular cells in Ang II-infused rats. In contrast, the principal effect of Ang II in glomeruli was to increase the expression of alpha-smooth muscle actin by mesangial cells and desmin by visceral glomerular epithelial cells. Ang II-infused rats also developed focal tubulointerstitial injury, with tubular atrophy and dilation, cast formation, an interstitial monocytic infiltrate, and mild interstitial fibrosis with increased type IV collagen deposition. The injury was associated with a proliferation of distal tubule, collecting duct, and interstitial cells as determined by immunostaining for proliferating cell nuclear antigen, and was accompanied by an increase in platelet-derived growth factor B-chain messenger RNA in the area of interstitial injury as localized by in situ hybridization. Renal interstitial cells also underwent phenotypic modulation in which they expressed alpha-smooth muscle actin. Vehicle-infused control rats displayed no tubular injury, proliferation, or phenotypic modulation. Thus, Ang II in doses that cause moderate hypertension induces marked vascular, glomerular, and tubulointerstitial injury with cell proliferation, leukocyte recruitment, phenotypic modulation with the upregulation of proteins normally associated with smooth muscle cells, and interstitial fibrosis.

Angiotensin II↗
PubMed1990

Modulation of phosphoinositide metabolism in aortic smooth muscle cells by allylamine.

Aortic smooth muscle cells (SMC) modulate from a contractile to a proliferative phenotype upon subchronic exposure to allylamine. The present studies were designed to determine if this phenotypic modulation is associated with alterations in the metabolism of membrane phosphoinositides. 32P incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidic acid (PA) was lower by 31, 35, and 22%, respectively, in SMC from allylamine-treated animals relative to controls. In contrast, incorporation of [3H]myoinositol into inositol phosphates did not differ in allylamine cells relative to control cells. Exposure to dibutyryl (db) cAMP (0.2 mM) and theophylline (0.1 mM) reduced 32P incorporation into PIP and PIP2 in SMC from both experimental groups. Under these conditions, a decrease in [3H]myoinositol incorporation into inositol 1-phosphate was only observed in allylamine cells. The effects of db cAMP and theophylline in allylamine and control SMC correlated with a marked decrease in cellular proliferation. These results suggest that alterations in phosphoinositide synthesis and/or degradation contribute to the enhanced proliferation of SMC induced by allylamine. To further examine this concept, the effects of agents which modulate protein kinase C (PKC) activity were evaluated. Sphingosine (125-500 ng/ml), a PKC inhibitor, decreased SMC proliferation in allylamine, but not control cells. 12-O-Tetradecanoylphorbol-13-acetate (1-100 ng/ml), a PKC agonist, stimulated proliferation in control cells, but inhibited proliferation in cells from allylamine-treated animals. We conclude that allylamine-induced phenotypic modulation of SMC is associated with alterations in phosphoinositide metabolism.

Allylamine↗
PubMed1993

Tumour necrosis factor-alpha can modulate the phenotype of aortic smooth muscle cells.

In culture, rabbit aortic smooth muscle cells (SMC) from an atheroma differed phenotypically from SMC from normal media (M-SMC) in their growth rate, secretion of SMC-derived growth factor (SDGF), and metabolism of acetylated low density lipoproteins (a-LDL). The factor responsible for this in vivo phenotypic change of SMC was investigated in vitro. After preincubation of M-SMC with 0.1-10 U ml-1 of tumour necrosis factor-alpha (TNF) for 1-3 days, the cells grew faster than control cells and secreted a substantial amount of SDGF. The population doubling time and secretion of SDGF were inversely correlated. Moreover, after preincubation with TNF, the SMC metabolized [125I]a-LDL, unlike control M-SMC. These findings show that TNF can modulate the phenotype of SMC and suggest that it is important in the pathogenesis of atherosclerosis.

Animals↗
PubMed1991

[Modulation of arterial smooth muscle cells in culture and cholesterol exchange].

The phenotypic modulation and the enhanced proliferation of smooth muscle cells (SMC) as well as their foam transformation are major processes in arterial pathophysiology and during atherogenesis. Arterial SMC play a crucial role, in response to several stimuli: the SMC "activation" is an essential condition leading to the adult atherosclerotic plaque formation. Owing to the difficulty to study the SMC regulation in vivo, most of the literature in this field refers to in vitro models. Modulated SMC in culture, changing from a contractile to a synthetic state, share similar features with atherosclerotic plaques cells. The phenotypic modulation of SMC is expressed by morphological, biochemical, metabolic and functional modifications. The regulation of cholesterol movements might influence the foam transformation process of arterial SMC.

Animals↗
PubMed1997

[Role of the renin-angiotensin system in cardiovascular and renal diseases].

Accumulating evidence indicate that various growth-related genes, growth factors and extracellular matrix components play a central role in the pathogenesis of cardiovascular and renal diseases by regulating cellular phenotype, growth and migration or promoting tissue fibrosis. Treatment of hypertensive rats with an angiotensin II type 1-receptor (AT1-receptor) antagonist normalizes cardiac phenotypic modulation and the increased fibrosis-related gene expressions in hypertrophied heart, leading to the improvement of cardiac dysfunction. The AT1-receptor antagonist can inhibit protooncogenes (c-fos, c-jun and Egr-1) and fibronectin gene expressions in rat balloon-injured artery, which is associated with the inhibition of neointima formation. Furthermore, the AT1-receptor antagonist prevents either the phenotypic modulation of glomerular mesangial cells or the increase in transforming growth factor-beta 1 expression in nephrosclerosis. Thus, the AT1-receptor antagonist in vivo potently inhibits the expression of growth-related gene and extracellular matrix and inhibits cellular phenotypic modulation. The AT1-receptor is responsible for the pathogenesis and development of cardiovascular and renal diseases.

Angiotensin Receptor Antagonists↗
PubMed1988

Modulation of phenotypic and functional properties of human peripheral blood monocytes by IL-4.

Highly purified peripheral blood monocytes were cultured in the presence of rIL-4. Major changes in the morphology of the monocytes were observed. After day 5 of culturing the cells acquired a macrophage-like appearance, with increased cell size and extensive processes, suggesting that IL-4 may induce monocyte-macrophage differentiation. This notion is supported by the observed increased expression of MHC class II Ag, which is thought to be associated with monocyte differentiation. Exposure of monocytes to IL-4 resulted in a dose-dependent increase of the expression of MHC class II Ag, which became apparent after only 20 h of incubation. Maximal expression was obtained after incubation for 6 days, and persisted throughout the whole culture period. Similarly, IL-4 increased the expression of R for C3bi and p150.95 Ag, two members of the leukocyte function-associated Ag 1 family, whereas the expression of the third member, leukocyte function-associated Ag 1, remained unchanged during culture. Furthermore, it was shown that IL-4 inhibited the secretion of cytostatic and chemotactic compounds. Supernatants of monocytes cultured with IL-4 were, in contrast to control cultures, much less effective in inhibiting the growth of A375 melanoma cells. In addition, these supernatants failed to direct the migration of freshly isolated monocytes in a chemotaxis assay. Further analysis revealed that these supernatants exhibited reduced IL-1 activity, as measured in a mouse thymocyte proliferation assay, which might explain the low cytostatic and chemotactic activity. Taken together these results show that IL-4 modulates monocyte phenotype and function and may induce monocyte-macrophage differentiation in vitro.

Antigens, Surface↗
PubMed1996

Regulation of proliferative response of cardiac fibroblasts by transforming growth factor-beta 1.

Cardiac fibroblasts constitute greater than 90% of the non-myocyte cells in the heart. Previously, it was established that cardiac fibroblasts are predisposed to transformation into a phenotype with muscle-specific features and that transforming growth factor-beta 1 (TGF-beta 1) is a specific inducer of this event. In this study the hypothesis that TGF-beta 1-induced phenotypic modulation of cardiac fibroblasts is associated with their altered proliferative capacity is tested. Therefore the effects of TGF-beta 1 on DNA synthesis in cardiac fibroblasts under normal conditions of cell culture and in response to a potent mitogen, basic fibroblasts growth factor (bFGF) were determined. The results showed that TGF-beta 1 at 15 ng/ml (a concentration that induces fibroblast "transformation") had a regulatory effect on proliferative capacity of cardiac fibroblasts which varied as the function of cell density in culture. In subconfluent and confluent cultures, pre-treatment of cardiac fibroblasts with TGF-beta 1 for 24 h resulted in a dramatic shift in the bFGF-induced stimulation of DNA synthesis. TGF-beta 1-induced inhibition of DNA synthesis in cardiac fibroblasts coincided with their phenotypic modulation as evidenced by the expression of sarcomeric actin mRNA and morphological changes. Cross-linking studies with [125I]-labeled TGF-beta 1 showed the presence of conventional types I, II and III TGF-beta 1 receptor complexes on cardiac fibroblasts and their binding to TGF-beta 1 under the experimental conditions. In summary, these data indicate that the proliferative capacity of cardiac fibroblasts is controlled by TGF-beta 1. They further suggest that the TGF-beta 1-induced phenotypic modulation of cardiac fibroblasts may be extended to include their altered proliferative capacity.

Actins↗
PubMed1992

Human macrophages modulate the phenotype of cultured rabbit aortic smooth muscle cells through secretion of platelet-derived growth factor.

Phenotypic change of aortic smooth muscle cells (SMC) is a key step for their abnormal proliferation in atheromatous lesions. In this study modulation of the growth properties of SMC by macrophages was investigated to clarify the mechanism regulating the SMC phenotype. Cultured rabbit SMC preincubated with either macrophages derived from human peripheral monocytes, or conditioned medium from macrophages grew faster than control SMC in the absence of either macrophages or conditioned medium. SMC preincubated with purified platelet-derived growth factor (PDGF) also grew faster than control SMC in the absence of PDGF, and their rapid growth was maintained for at least two passages. SMC preincubated with conditioned medium of macrophages plus anti-PDGF antibody did not grow faster than control SMC. Furthermore SMC preincubated with PDGF acquired the ability to secrete some mitogen, which differed from PDGF. These results suggest that macrophages modulate the phenotype of SMC by a mechanism mediated by PDGF. As a result the SMC grow faster and at the same time secrete some mitogen probably distinct from PDGF in an autocrine manner.

Animals↗
PubMed2000

Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for mechanism and potential modulation of phenotype.

Missense mutations account for 48% of all reported human disease-causing alleles. Since few are predicted to ablate directly an enzyme's catalytic site or other functionally important amino acid residues, how do most missense mutations cause loss of function and lead to disease? The classic monogenic phenotype hyperphenylalaninemia (HPA), manifesting notably as phenylketonuria (PKU), where missense mutations in the PAH gene compose 60% of the alleles impairing phenylalanine hydroxylase (PAH) function, allows us to examine this question. Here we characterize four PKU-associated PAH mutations (F39L, K42I, L48S, I65T), each changing an amino acid distant from the enzyme active site. Using three complementary in vitro protein expression systems, and 3D-structural localization, we demonstrate a common mechanism. PAH protein folding is affected, causing altered oligomerization and accelerated proteolytic degradation, leading to reduced cellular levels of this cytosolic protein. Enzyme specific activity and kinetic properties are not adversely affected, implying that the only way these mutations reduce enzyme activity within cells in vivo is by producing structural changes which provoke the cell to destroy the aberrant protein. The F39L, L48S, and I65T PAH mutations were selected because each is associated with a spectrum of in vivo HPA among patients. Our in vitro data suggest that interindividual differences in cellular handling of the mutant, but active, PAH proteins will contribute to the observed variability of phenotypic severity. PKU thus supports a newly emerging paradigm both for mechanism whereby missense mutations cause genetic disease and for potential modulation of a disease phenotype.

ATP-Binding Cassette Transporters↗
PubMed1989

In vitro study of translocation t(4;11) acute leukemia. Sequential range of phenotype.

The nature of translocation t(4;11) acute leukemia cells has been widely discussed over the past few years. Many authors report their phenotypic heterogeneity, ranging from apparently common acute lymphoblastic leukemia antigen-positive to monoblastic leukemia, through "promiscuous" phenotype. We studied in vitro phenotypic modulation of three typical cases after induction by 12-O-tetradecanoyl phorbol 13 acetate. The initial phenotype was different in each case, but all of them exhibited changes in morphologic shape, cytochemistry, and immunophenotype; common features appeared after induction by 12-O-tetradecanoyl phorbol 13 acetate, including esterase activity, expression of CD-9, CD-15, and CD-18 surface antigens, and monocyte/macrophage morphology. In all cases a B-associated surface antigen, CD-19, persisted. During clinical evolution, some previously reported cases have shown a karyotypic and phenotypic transformation. In one of our cases this phenomenon correlated with in vitro phenotypic modulation of initial blast population. Furthermore, clinical relapses and in vitro modulation always seem to evolve toward a more "mature" phenotype. Those results support the "promiscuous lineage" hypothesis, and point out the usefulness of in vitro studies to express the myeloid potential of this category of acute leukemia, which can be regarded as a model of early hematopoietic differentiation.

Acute Disease↗
PubMed2005

Genetic reprogramming of tumor cells by zinc finger transcription factors.

Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drug-resistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires co-regulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By co-regulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes.

Animals↗