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PubMed1999

The Notch-Hes pathway in mammalian neural development.

A wide variety of neurons and glial cells differentiate from common precursor cells in the developing nervous system. During this process, Notch-mediated cell-cell interaction is essential for maintenance of dividing cells and subsequent generation of cell type diversity. Activation of Notch inhibits cellular differentiation, and abnormality of the Notch pathway leads to premature neuronal differentiation, the lack of some cell types, and severe defects of tissue morphogenesis. Recent data demonstrate that Notch fails to inhibit cellular differentiation in the absence of the bHLH genes Hes1 and Hes5, which functionally antagonize the neuronal bHLH genes such as Mash1. These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway "Notch-Hes1/Hes5-|Mash1".

Animals↗

PubMed1995

Mechanism of interferon beta-induced squamous differentiation and programmed cell death in human non-small-cell lung cancer cell lines.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality due largely to the failure of systemic chemotherapy. Thus, new therapeutic paradigms involving the manipulation of normal physiologic growth-regulatory mechanisms, such as terminal cellular differentiation or programmed cell death, are being explored. Interferons may function as antineoplastic agents, in part because of their effects on cell proliferation and differentiation. We have previously demonstrated the antiproliferative and differentiating effects of interferon beta (IFN beta). PURPOSE: The present investigation was designed to study the mechanism of IFN beta on squamous differentiation and/or programmed cell death in cultured NSCLC cells. METHODS: Cross-linked envelope competence and transglutaminase expression and activity were measured in three NSCLC cell lines (NCI-H226, NCI-H358, and NCI-H596) as common markers for squamous differentiation and programmed cell death. DNA fragmentation, as determined by gel electrophoretic analysis, served as a marker for programmed cell death. In addition, the expression of several regulatory and differentiation-related genes (measured by Northern blot analysis of messenger RNA levels) as well as protein kinase C activity was measured to begin to explore possible mechanisms of IFN beta activity. RESULTS: IFN beta-induced cross-linked envelope competence occurred in cell lines with squamous features (NCI-H226 and NCI-H596); conversely, DNA fragmentation occurred in cell lines with glandular features (NCI-H358 and NCI-H596). Stimulation of cross-linked envelope competence by IFN beta was associated with the induction of tissue transglutaminase activity. Both of these parameters were protein-synthesis independent. As previously observed for NCI-H596, IFN beta suppressed the growth of the other two cell lines. Total protein kinase C activity was not altered. Expression of a variety of possibly relevant oncogenes and other genes was variably altered by IFN beta. CONCLUSIONS: IFN beta induces programmed cell death in NSCLC cell lines in a phenotype-specific manner. The programmed cell death pathway represented by cross-linked envelope competence is dependent on the expression of the squamous phenotype and is protein-synthesis independent, suggesting post-translational mechanisms. In addition, squamous differentiation itself may be induced. Changes in gene expression, while not necessary for induction of cross-linked envelope competence, may be involved in other aspects of cellular homeostasis, such as growth suppression. IMPLICATIONS: By inducing terminal cellular differentiation or programmed cell death, IFN beta may be therapeutically useful in NSCLC. The post-translational nature of IFN beta-induced effects suggests that it will be best used in combination with other agents that can regulate these cellular pathways at the pretranslational level, increasing the proportion of cells capable of being driven to a terminal state by this biotherapeutic agent.

Apoptosis↗

PubMed1995

Differential cell analysis and phenotypic subtyping of lymphocytes in bronchoalveolar lavage fluid from clinically normal dogs.

In 33 healthy dogs, 66 bronchoalveolar lavage samples from the right and left caudal lung lobes were analyzed for volume of return, cellularity, differential cellularity, and immunophenotypic lymphocyte subpopulations. Lavage return was 64.8% (mean) following 3 sequential 25-ml lavages, for a total lavage volume of 75 ml. With this technique, 21.1 x 10(6) cells/sample (mean) were obtained. The cellular components of bronchoalveolar lavage samples, in decreasing order of frequency, were alveolar macrophages (79.4%), lymphocytes (13.5%), eosinophils (3.6%), mast cells (2.1%), epithelial cells (0.8%), and neutrophils (0.6%). Mean alveolar lymphocyte subpopulation frequencies, determined in 18 samples, for pan T, CD4, and CD8 cells were 52, 21.9, and 17.8%, respectively, with a CD4/CD8 ratio of 1.3. Variables analyzed did not vary between right and left caudal lung lobes, nor were they affected by body weight.

Animals↗

PubMed1992

Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways.

Vascular endothelial growth factor (VEGF) is an angiogenic polypeptide that has been isolated from a variety of tumorigenic and nontransformed cell lines. Because of the importance of blood vessel growth to cell and tissue development, we have examined VEGF gene expression in a variety of mouse tissues and rodent models of cellular differentiation. Using a cloned murine VEGF cDNA we show that VEGF mRNA is expressed at relatively low levels in many adult mouse tissues examined. However, this message is dramatically induced in two models of cell differentiation: 3T3-adipose conversion and C2C12 myogenic differentiation. VEGF protein secretion is also induced in adipocyte differentiation. VEGF mRNA is markedly regulated in a pheochromocytoma (PC12) cell model of transformation and differentiation. The transformed undifferentiated cells express moderate levels of VEGF mRNA and this expression is virtually extinguished when cells differentiate into non-malignant neuron-like cells. Experiments employing phorbol esters and cAMP analogues indicate that VEGF mRNA expression is stimulated in preadipocytes by both protein kinase C and protein kinase A-mediated pathways. These results suggest that VEGF mRNA levels are closely linked to the process of cellular differentiation; they also clearly demonstrate that expression of this angiogenic factor is specifically regulated in a transformed cell line, possibly via aberrant activation of cellular second messenger pathways.

3T3 Cells↗

PubMed1999

Forced expression of the homeobox-containing gene Pem blocks differentiation of embryonic stem cells.

Similarities in the differentiation of mouse embryos and ES cell embryoid bodies suggest that aspects of early mammalian embryogenesis can be studied in ES cell embryoid bodies. In an effort to understand the regulation of cellular differentiation during early mouse embryogenesis, we altered the expression of the Pem homeobox-containing gene in ES cells. Pem is normally expressed in the preimplantation embryo and expressed in a lineage-restricted fashion following implantation, suggesting a role for Pem in regulating cellular differentiation in the early embryo. Here, we show that the forced expression of Pem from the mouse Pgk-1 promoter in ES cells blocks the in vitro and in vivo differentiation of the cells. In particular, embryoid bodies produced from these Pgk-Pem ES cells do not differentiate into primitive endoderm or embryonic ectoderm, which are prominent features of early embryoid bodies from normal ES cells. This Pgk-Pem phenotype is also different from the null phenotype, as embryoid bodies derived from ES cells in which endogenous Pem gene expression has been blocked show a pattern of differentiation similar to that of normal ES cells. When the Pgk-Pem ES cells were introduced into subcutaneous sites of nude mice, only undifferentiated EC-like cells were found in the teratomas derived from the injected cells. The Pem-dependent block of ES cell differentiation appears to be cell autonomous; Pgk-Pem ES cells did not differentiate when mixed with normal, differentiating ES cells. A block to ES cell differentiation, resulting from the forced expression of Pem, can also be produced by the forced expression of the nonhomeodomain region of Pem. These studies are consistent with a role for Pem in regulating the transition between undifferentiated and differentiated cells of the early mouse embryo.

Animals↗

PubMed2004

Microarray analysis of differentiation-specific gene expression during 3T3-L1 adipogenesis.

During cellular differentiation and development, it is recognized that many complex molecular mechanisms as well as precise patterns of differentially expressed genes occur in directing precursor cells toward a given lineage. Using microarray-based technology, we examined gene expression across the course of 3T3-L1 adipocyte differentiation. Total cellular RNA was isolated at times 0, 2, 8, 16, 24, 48, and 96 h following treatment with either standard hormonal inducers of differentiation; insulin, dexamethasone, isobutylmethylxanthine (IDX), or IDX plus trichostatin A (TsA), a histone deacetylase inhibitor and potent adipogenic inhibitor. cRNA was synthesized from cellular RNA and hybridized to high density Affymetrix MG_U74Av2 microarray gene chips containing 12,488 cDNA/Expressed Sequence Tags (ESTs) probe sets. From the IDX-only treated cells, all probe sets that were either unchanged or differentially expressed less than 2-fold throughout differentiation with respect to time 0 preadipocytes were excluded from further analyses. This selection resulted in a net of 1686 transcripts, 859 were increased in expression, and 827 were decreased in expression at least 2-fold across differentiation. To focus in on genes that were more specific to differentiation, the same analysis was performed on IDX plus TsA-treated non-differentiating cells and all probe sets from the IDX-only group that exhibited similar expression profiles in the non-differentiating TsA-treated group were excluded leaving a total of 1016 transcripts that were regulated only under differentiating conditions. Six hundred and thirty-six of these transcripts were elevated at least 2-fold and 380 exhibited a decrease in expression relative to time 0 preadipocytes. This group of genes was further analyzed using hierarchical clustering and self-organizing maps and resulted in the identification of numerous genes not previously known to be regulated during adipocyte differentiation. Many of these genes may well represent novel adipogenic mediators and markers of adipogenesis.

1-Methyl-3-isobutylxanthine↗

PubMed2002

Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation.

The active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] is key mediator of calcium homeostasis and is a component of the complex homeostatic system of the skin. 1,25-(OH)2D3 regulates cellular differentiation and proliferation and has broad potential as an anticancer agent. Oligonucleotide microarrays were used to assess profiles of target gene regulation at several points over a 48 h period by the low calcemic 1,25-(OH)2D3 analog EB1089 in human SCC25 head and neck squamous carcinoma cells. One hundred fifty-two targets were identified, composed of 89 up- and 63 down-regulated genes distributed in multiple profiles of regulation. Results are consistent with EB1089 driving SCC25 cells toward a less malignant phenotype, similar to that of basal keratinocytes. Targets identified control inter- and intra-cellular signaling, G protein-coupled receptor function, intracellular redox balance, cell adhesion, and extracellular matrix composition, cell cycle progression, steroid metabolism, and more than 20 genes modulating immune system function. The data indicate that EB1089 performs three key functions of a cancer chemoprevention agent; it is antiproliferative, it induces cellular differentiation, and has potential genoprotective effects. While no evidence was found for gene-specific differences in efficacy of 1,25-(OH)2D3 and EB1089, gene regulation by 1,25-(OH)2D3 was generally more transient. Treatment of cells with 1,25-(OH)2D3 and the cytochrome P450 inhibitor ketoconazole produced profiles of regulation essentially identical to those observed with EB1089 alone, indicating that the more sustained regulation by EB1089 was due to its resistance to inactivation by induced 24-hydroxylase activity. This suggests that differences in action of the two compounds arise more from their relative sensitivities to metabolism than from differing effects on VDR function.

Biomarkers, Tumor↗

PubMed2006

alpha-Synuclein stimulates differentiation of osteosarcoma cells: relevance to down-regulation of proteasome activity.

Because a limited study previously showed that alpha-synuclein (alpha-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether alpha-syn might be involved in the regulation of tumor differentiation. For this purpose, alpha-syn and its non-amyloidogenic homologue beta-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with beta-syn-overexpressing and vector-transfected cells, alpha-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in alpha-syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In alpha-syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in alpha-syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of alpha-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of alpha-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of alpha-syn regulation of tumor differentiation and neuropathological effects of alpha-syn may considerably overlap with each other.

Autophagy↗

PubMed2004

Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis.

Magnetic resonance (MR) tracking of superparamagnetic iron oxide (SPIO)-labeled cells is a relatively new technique to non-invasively determine the biodistribution and migration of transplanted stem cells. A number of studies have recently reported encouraging results in the use of bone marrow-derived mesenchymal stem cells (MSCs) for repair of a variety of tissues. For MR tracking of SPIO-labeled MSCs, it is important to determine the effect that the magnetic labeling procedure may have on the differentiation capacity of labeled MSCs. Human MSCs were labeled with poly-L-lysine (PLL)-coated Feridex, with Feridex being an FDA-approved SPIO formulation in an off-label application, and assayed for cellular differentiation using five different assays. As compared with unlabeled controls, labeled MSCs exhibited an unaltered viability, proliferated similarly, and underwent normal adipogenic and osteogenic differentiation. However, there was a marked inhibition of chondrogenesis. The blocking of chondrogenic activity was mediated by the Feridex, rather than by the transfection agent (PLL). This is the first report showing Feridex blocking of cellular differentiation down a specific pathway (while not affecting viability and proliferation), and caution should thus be exercised when using Feridex-labeled MSCs for chondrogenic MR tracking studies. On the other hand, no detrimental effects of Feridex-labeling are anticipated for MR-guided osteogenic or adipogenic transplantation studies.

Adipocytes↗

PubMed1996

High Sp1/Sp3 ratios in epithelial cells during epithelial differentiation and cellular transformation correlate with the activation of the HPV-16 promoter.

Gene expression of human papillomavirus type 16 (HPV-16) and other HPV types is epithelial specific. Specificity is brought about by synergism between several different transcription factors that seem to occur ubiquitously but differ qualitatively and quantitatively between cells in which HPV genomes are transcriptionally active or inactive. Here, we report on the contribution to this combinatorial mechanism by the activator Sp1 and the related antagonist Sp3, both of which can bind a single site at the E6 promoter of all genital HPVs. In the Sp-factor-free background of Drosophila cells, Sp1 activates HPV-16 transcription, while Sp3 fails to do so and even inhibits the activation by Sp1. The same differential activation occurs in the case of promoters of the epithelial-specific cellular genes encoding keratin 18 and E-cadherin. All cell types that we examined contain similar amounts of Sp3 factor. In contrast, Sp1 levels, determined by supershifts and Western blots, are higher in several human epithelial cell lines that support HPV transcription than in human fibroblasts, liver, and muscle cells. This suggests that cell-type differential transcription is regulated by Sp1 and Sp3. In primary keratinocytes, Sp3 levels exceed those of Sp1. This ratio became inverted after differentiating these cells in high calcium, or methyl cellulose containing medium. The simultaneous transcriptional stimulation of the HPV promoter points to a role of the Sp1-Sp3 antagonism during a differentiation of stratified epithelia in vivo, as these culture techniques mimick this process in vitro. Transformation in vivo or in vitro seems to override these cell-type-specific controls and leads to a general increase of Sp1 activity.

Animals↗

PubMed2004

Histone deacetylase inhibitors up-regulate the expression of tight junction proteins.

Histone deacetylase (HDAC) inhibitors promote cell maturation, differentiation, and apoptosis through changes in gene expression. Differentiated epithelial cells are characterized by apical tight junctions (TJ), which play a role in cell-cell adhesion, polarity, and the permeability barrier function of epithelia. The relationship between cellular differentiation and expression of TJ-associated proteins is not known. Here, we investigated whether HDAC inhibitors affect the expression of TJ proteins in cultured cells by immunoblotting, immunofluorescence, and quantitative real-time, reverse transcription-PCR. We find that the HDAC inhibitor sodium butyrate significantly up-regulates the protein levels of cingulin, ZO-1, and ZO-2 in Rat-1 fibroblasts, cingulin in COS-7 cells, and cingulin and occludin in HeLa cells. Levels of mRNA for cingulin, ZO-1, and ZO-2 are also increased in sodium butyrate-treated Rat-1 fibroblasts. Up-regulation of cingulin is reversible and dose dependent and requires de novo protein synthesis and protein kinase activity, because it is inhibited by cycloheximide and by the protein kinase inhibitor H-7. Up-regulation of TJ proteins by sodium butyrate is linked to the ability of sodium butyrate to inhibit HDAC activity, because suberoylanilide hydroxamic acid, a HDAC inhibitor of a different structural class, also up-regulates cingulin, ZO-1, and ZO-2 expression in Rat-1 fibroblasts. These results indicate that cellular differentiation correlates with kinase-dependent up-regulation of the expression of specific TJ proteins.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1988

Early events in murine erythroleukemia cells induced to differentiate. Accumulation and gene expression of the transformation-associated cellular protein p53.

Oncogenes may play a crucial role in the genetic program of cellular differentiation; even, probably, at a very early stage in this program, which can be described as pre-commitment. We have investigated the variation in, and the control level of, the accumulation of the transformation-associated cellular protein p53 in murine erythroleukemia cells induced to differentiate by hexamethylene bisacetamide. Using flow cytofluorimetry after double staining of the cells, we have found that p53 decreased from two hours after the input of the inducer, to reach a basal level of about 30% of the starting value. The stability of the protein was found to be affected neither by the inducer nor by the position of the cells in the cell cycle. Looking for the regulation mechanism of the p53 decay, we found that the mRNA started to decrease as early as half an hour after the hexamethylene bisacetamide was put in the culture medium, and that the transcription rate of the gene itself could not account for the observed down-regulation of the mRNA, suggesting a post-transcriptional control for the mRNA accumulation. This control did not require the de-novo synthesis of a protein component, as shown by cycloheximide experiments, but seemed to be governed by the induced synthesis of an RNA molecule. Hypothetical models for such a regulation process are discussed in the light of recent reports on the metabolism of mRNA.

Acetamides↗

PubMedDate not supplied

Diagnosis of bronchogenic carcinoma through the cytologic examination of sputum, with special reference to tumor typing.

The results obtained in the cytologic study of sputa from 630 patients are presented. There were 251 cases of bronchogenic carcinoma; diagnosis through sputum examination was possible in 57.4 per cent of the patients. Abnormal cells were detected in an additional 24.3 per cent. Sputum examination has proven to be a valuable complement by establishing the correct diagnosis when other methods failed. Cancer cells were unequivocally identified in 45.8 per cent of the cases with normal bronchoscopic examination and in 52.4 per cent of the cases in which bronchial biopsy did not include malignant tissue. The same proportion of cases with the various tumor types was obtained by cytologic and by histologic study. However, one of the methods often showed a higher degree of cellular differentiation than the other. The number of cases with undifferentiated cancer or unclassified tumors was markedly reduced when the information concerning cell differentiation available through both methods was used. In this manner, excluding the oat cell carcinomas, only 7.6 per cent of the cases of bronchogenic carcinoma did not show any cellular differentiation. The authors recommend wider use of the information provided by simultaneous evaluation of both cytologic smears and tissue sections in order to achieve a more accurate appraisal of tumor type.

Adenocarcinoma↗

PubMed2005

Effect of electromagnetic fields on proliferation and differentiation of cultured mouse bone marrow mesenchymal stem cells.

In order to study the effects of electromagnetic fields (EMFs) on proliferation, differentiation and intercellular cyclic AMP (cAMP) in mouse bone marrow mesenchymal stem cells (MSCs) in vitro, the mouse bone MSCs were isolated and cultured in vitro. The third passage MSCs were divided into 4 groups and stimulated with EMFs. The cellular proliferation (MTT), the cellular differentiation (alkaline phosphatase activity, ALP), and the intercellular cAMP level were investigated at different time points. The results showed that EMF (50Hz pulse burst 2 mT peak) inhibited the cellular proliferation (P < 0.05), enhanced the cellular differentiation (P < 0. 05), and increased the intercellular cAMP level (P < 0.01) in the early time of the stimulation (1-3 days), but the intercellular cAMP level did not increased further in the later days. We are led to conclude that the cAMP may be involved in the mediation of the growth inhibitory and differentiation-inducing signals of specific EMFs in vitro.

Alkaline Phosphatase↗

PubMed1995

Cytoskeleton gradients in three dimensions during neurulation in the rabbit.

Morphogenetic movements leading to the formation of the neural tube and cellular differentiation leading to neuronal and glial cell lineages are both part of early development of the vertebrate nervous system. In order to analyze the degree of overlap between these processes, cellular differentiation during the shaping of the neural plate is investigated immunohistochemically by using monoclonal intermediate filament protein antibodies and the 7.5-8.0-day-old rabbit embryo as a model. Western blotting is used to confirm the specificity of the antibodies, which include a new monoclonal vimentin antibody suitable for double-labeling in combination with monoclonal cytokeratin (and fibronectin) antibodies. Starting in the early somite embryo and concomitant with neural plate folding, a gradual loss of cytokeratin 8 (and 18) expression in the neuroepithelium is mirrored by a gain in vimentin expression with partial coexpression of both proteins. At the prospective rhombencephalic and spino-caudal levels, vimentin expression, in particular, changes (i.e., increases) along gradients in three dimensions: along the longitudinal axis of each neuroepithelial cell from basal to apical, in the transverse plane of the embryo from dorsolateral to ventromedial and along the craniocaudal axis from prospective rhombencephalic toward spino-caudal levels of the neural plate. At the prospective mes- and prosencephalic levels, the expression change also proceeds from basal to apical within each neuroepithelial cell, but along the other axes described here, the progress in expression change is more complex. Although the functional meaning of these highly ordered expression changes is at present unclear, the gradients suggest a novel pattern of neuroepithelial differentiation which may be functionally related to the process of interkinetic nuclear migration (Sauer [1935] J. Comp. Neurol. 62:377-402) and which partially coincides with the morphogenetic movements involved in the shaping of the neural plate.

Animals↗

PubMed1993

Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation.

Human hepatocellular carcinoma (HCC) often contains intratumoral subpopulations of heterogeneous cellular differentiations within each tumor. To analyze the genetic alterations of p53 in the heterogeneous subpopulations, we examined 68 intratumoral nodular lesions within 34 HCCs composed of two distinct subpopulations. The cellular differentiations were determined histologically by Edmondson's grading system. Nine (26.5%) of 34 HCCs examined were found to have genetic alterations in exons 5 to 8 of the p53 gene, resulting in amino acid substitutions. Three of these nine HCCs with p53 mutations showed genetic heterogeneity of the p53 gene within each tumor; one HCC had a single missense mutation at codon 210 (asparginine to 210-serine) in an intratumoral lesion of Edmondson Grade II and double missense mutations at codons 210 and 217 (asparginine to 210-serine and valine to 217-alanine) in another intratumoral lesion of Edmondson Grade III. The remaining two HCCs had p53 mutations only in lesions of a higher grade. In total, the p53 mutations were detected in none of eight Edmondson Grade I lesions, in five of 29 Grade III lesions (17.2%), in eight of 26 Grade III lesions (30.8%), and in three of five Grade IV lesions (60.0%). Thus, our data revealed that the p53 mutations were closely related to the progression of HCC and that, in certain cases, malignant cells which acquired the p53 mutations might develop into dedifferentiated subpopulations within individual HCC.

Amino Acid Sequence↗

PubMed1989

Mononuclear cell polyamine content associated with myeloid maturation in patients with leukemia during administration of polyamine inhibitors.

Fourteen patients with acute leukemia in relapse were treated with difluoromethylornithine (DFMO) alone or in combination with methylglyoxal-bis(guanylhydrazone) (MGBG) as part of Phase I studies. Five patients included in the trial exhibited morphologic evidence of cellular differentiation during the course of treatment. In one patient who exhibited no blasts and a normal white blood cell differential at the end of treatment the mononuclear cell content of all three polyamines declined after an initial increase in spermidine and spermine content. In the other patients in whom the cellular maturation was less pronounced the mononuclear cell polyamine levels remained stable or increased over the treatment time. No absolute difference was apparent between the cellular polyamine levels detected in patients at the times of the greatest increase in per cent circulating neutrophils as compared to the cellular levels present in patients whose circulating mononuclear cell number were increasing. Circulating mononuclear cell putrescine, spermidine, and spermine levels varied over two orders of magnitude from patient to patient and the range of values detected in each state completely overlapped those present in the other. It does not appear from the present study that there is a consistent human leukemic cell polyamine content at which cellular differentiation occurs.

Adolescent↗

PubMed2004

Differentiate to thrive: lessons from the Legionella pneumophila life cycle.

When confronted by disparate environments, microbes routinely alter their physiology to tolerate or exploit local conditions. But some circumstances require more drastic remodelling of the bacterial cell, as sporulation by the Bacillus and Streptomyces species of soil bacteria vividly illustrates. Cellular differentiation is also crucial for pathogens, the challenge for which is to colonize one host, then be transmitted to the next. Using the Gram-negative Legionella pneumophila as a model intracellular pathogen, we describe how biogenesis of the replication vacuole is determined by the developmental state of the bacterium. Subsequently, when replicating bacteria have exhausted the nutrient supply, the pathogens couple their conversion to stationary phase physiology with expression of traits that promote transmission to a new host. The cellular differentiation of L. pneumophila is co-ordinated by a regulatory circuit that integrates several elements that are broadly conserved in the microbial world. The alarmone (p)ppGpp promotes transcription directed by the alternative sigma factors RpoS, FliA and, probably, RpoN, and also post-transcriptional control mediated by a two-component regulatory system, LetA/S (GacA/S), and an mRNA-binding protein, CsrA (RsmA). By applying knowledge of microbial differentiation in combination with tools to screen the complete genomes of pathogens, experiments can be designed to identify two distinct classes of virulence traits: factors that promote replication and those dedicated to transmission.

Amoeba↗