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PubMed1988

Taurine and beta-alanine uptake in primary astrocytes differentiating in culture: effects of ions.

The effects of ions on taurine and beta-alanine uptake were studied in astrocytes during cellular differentiation in primary cultures. The uptakes were strictly Na+-dependent and also inhibited by the omission of K+ and in the presence of ouabain suggesting that their transport is fuelled mainly by these cation gradients. Two sodium ions were associated in the transport of one taurine and beta-alanine molecule across cell membranes. A reduction in Cl- concentration also markedly inhibited the uptake of both amino acids, indicating that this anion is of importance in the transport processes. The similar ion dependency profiles of taurine and beta-alanine uptake corroborate the assumption that the uptake of these amino acids in astrocytes is mediated by the same carrier. In Na+- and K+-free media both taurine and beta-alanine uptakes were reduced significantly more in 14-day-old or older than in 7-day-old cultures. No significant changes occurred in the coupling ratio between Na+ and taurine or beta-alanine as a function of spontaneous cellular differentiation or upon dBcAMP treatment. These results suggest that the uptake systems of these structurally related amino acids in astrocytes have reached a relatively high degree of functional maturity by two weeks in culture.

Alanine↗
PubMed1987

Metabolic adaptations in mouse mammary gland during a normal lactation cycle and in extended lactation.

The development and involution of mouse mammary tissue was measured in terms of changes in the cell population and the synthetic capacity of cells during the course of pregnancy, lactation and natural weaning, and after lactation was extended by introduction of foster litters of younger pups. Synthetic capacity was assessed by measuring the activities of several key enzymes closely concerned with the synthesis of milk constituents together with other constitutive enzymes. The capacity of the tissue to synthesize lactose and casein was also measured using short-term cultures of freshly prepared mammary explants. Results showed that the mammary cell population began to increase and differentiate around the time of parturition. Cell numbers increased up to day 5 of lactation, whereas cellular differentiation continued through lactation until day 15, around the time of peak milk yield. After day 15 there was a sharp drop, followed by a gradual decline in synthetic capacity and cell population, as pups were weaned. Substitution of younger pups for the natural litter at day 15 prevented the normal fall in milk secretion. In this case, mammary cell number remained at day 15 levels; cellular differentiation was also maintained to a considerable degree, although several markers of differentiation decreased during extended lactation.

Adaptation, Physiological↗
PubMed1993

Adult mouse kidneys become permissive to acute polyomavirus infection and reactivate persistent infections in response to cellular damage and regeneration.

Kidneys of newborn (but not adult) mice are normally high permissive for polyomavirus (Py) infection and readily establish persistent infections. We have proposed that ongoing cellular differentiation, which occurs in newborn mice, may be necessary for a high level of in vivo Py replication (R. Rochford, J. P. Moreno, M. L. Peake, and L. P. Villarreal, J. Virol. 66:3287-3297, 1992). This cellular differentiation requirement may also be necessary for the reactivation of a persistent Py kidney infection and could provide an alternative to the accepted view that reactivation results from immunosuppression. To examine this proposal, the ability of adult BALB/c mouse kidneys to support primary acute Py infection or to reactivate previously established persistent Py infections after kidney-specific damage was investigated. Kidney damage was induced by both chemical (glycerol, cisplatin, or methotrexate) and mechanical (through renal artery clamping to produce unilateral renal ischemia) treatments. We also examined the effects of epidermal growth factor (EGF), which enhances the rate of kidney regeneration, on Py replication. Using histopathologic techniques, in situ hybridization for Py DNA, and immunofluorescence for Py VP1 production, we established that both chemical damage and damage through renal artery clamping of adult kidneys promoted high levels of primary Py replication in these normally nonpermissive cells. This damage also promoted the efficient reactivation of Py replication from persistently infected kidneys, in the absence of immunosuppression. EGF treatment significantly increased acute Py replication and also reactivation in damaged kidneys. These results support the view that ongoing cellular division and differentiation may be needed both for high levels of acute Py replication and for reactivation of persistent infections in vivo.

Acute Disease↗
PubMed2003

The expression of cyclooxygenase in transitional cell carcinoma cell lines: its correlation with tumor differentiation, invasiveness and prostanoids production.

OBJECTIVE: To evaluate the isozyme activities of COX-1 and COX-2 in TCC cells and correlate with cellular differentiation and tumor behavior. MATERIAL AND METHODS: Various TCC cell lines were characterized through several aspects: (1). to measure the content and the mRNA amount of COX-1 and COX-2, (2). to characterize the proteins of COX-1 and COX-2 by Western immunoblotting, (3). to measure the production of prostaglandin E2 and thromboxane B2 in culture media, and (4). to correlate these parameters with tumor differentiation and invasiveness. RESULTS: Seven out of 10 cell lines (70%) had significantly higher COX expression than normal urothelium. Tumors with lower-grade differentiation and less invasiveness had significantly higher content of COX-1 and COX-2 than those tumors with higher-grade differentiation and more invasive behavior (p<0.01). The expression of COX mRNA in TSGH8301, TCC8702 and RT4 were much higher than J82 which has minimal expression of COXs. Similarly, the COX-2 protein was much higher in TSGH8301, TCC8702 and RT4 when compared with J82. TSGH8301, TCC8702, and RT4 had high production of PGE2 and thromboxane B2 in their culture media. Increased secretions of PGE2 and thromboxane B2 were also observed in TCC8701, TCC9101, HT1376, and T24. The production of prostanoids is closely related to cytoplasmic COX expression of tumor cells. CONCLUSIONS: The expression of COX-1 and COX-2 is a common phenomenon in TCC cells and closely related to cellular differentiation and tumor invasiveness. The COX-2 inhibitors may play an important role in the control of TCC growth.

Carcinoma, Transitional Cell↗
PubMed1986

Differentiation, dedifferentiation, and transdifferentiation of BALB/c 3T3 T mesenchymal stem cells: potential significance in metaplasia and neoplasia.

The expression of defects in the control of cellular differentiation is thought to be of etiological significance in the early stages of carcinogenesis. This possibility is supported by a variety of experimental studies including those that have established that metaplastic changes in cells can represent preneoplastic lesions in vivo. To evaluate this question in greater detail, we have used 3T3 T mesenchymal stem cells as a model system. These cells express certain characteristics of preneoplastic cells even though they can regulate their proliferation and even though they can undergo nonterminal and terminal differentiation into adipocytes. For example, they are immortal and aneuploid, and they show a proclivity to undergo spontaneous or induced neoplastic transformation compared to normal human cells. The question we sought to answer in the current experiments concerns whether predifferentiation growth arrest and/or nonterminal differentiation in such preneoplastic cells is completely reversible or whether these processes induce the expression of the new stable program that limits the cells' proliferative potential and reduces the cells' subsequent differentiation potential in a manner comparable to that which is thought to occur in normal stem cells. The results show that arrest at both the predifferentiation state and at the nonterminal differentiation state is a completely reversible phenomenon that does not limit the cells' subsequent growth or differentiation potential. In fact, the results show that, when nonterminally differentiated 3T3 T adipocytes are induced to dedifferentiate, they can subsequently redifferentiate into macrophages. We therefore suggest that preneoplasia as expressed in 3T3 T mesenchymal stem cells is associated with the expression of defects in the ability to integrally control cellular differentiation and proliferation. As a result, the data suggest that such cells express an increased proclivity to undergo metaplastic change and complete neoplastic transformation.

Adipose Tissue↗
PubMed1998

N,N-Dimethylformamide modulates acid extrusion from murine hepatoma cells.

N,N-Dimethylformamide (DMF) affects cellular differentiation, causes hepatotoxicity and gastric irritation, and may be carcinogenic. Since these processes involve changes in cellular pH homeostasis, we investigated the effects of DMF on H+ extrusion and cytosolic pH (pHi) of mouse hepatoma cells (Hepa 1C1C7). Extracellular pH was monitored using a silicon-based sensor system (Cytosensor microphysiometer) and pHi was monitored by fluorescence spectrophotometry. Superfusion of cells with DMF (0.25 to 0.5 M) suppressed the extracellular acidification rate (ECAR) below baseline. Following washout of DMF there was a rapid, concentration-dependent, prolonged overshoot of ECAR above baseline rates. Removal of extracellular Na+ or superfusion with amiloride abolished the overshoot in acidification rate, indicating involvement of Na+/H+ exchange. The overshoot was dependent on extracellular glucose, suggesting that it arises from an increase in metabolic acid production. Fluorescence measurements showed that DMF did not change pHi. Furthermore, DMF did not alter the rate of pHi recovery of cells acid loaded using nigericin, indicating that DMF does not directly alter Na+/H+ exchange activity in these cells. In summary, these data suggest that suppression of acidification rate by DMF is likely due to decreased metabolic acid production. Washout of DMF is then accompanied by increased glucose metabolism and H+ efflux via Na+/H+ exchange. It is possible that alterations in H+ production and transport contribute to the hepatotoxicity of DMF and its effects on cellular differentiation.

Amiloride↗
PubMed1988

Hypomethylation of DNA in the regulation of gene expression.

Although numerous possible functions of eukaryotic DNA methylation have been proposed (Ehrlich and Wang, 1981), current evidence suggests an association between hypomethylation of specific gene regions and transcriptional activity (Doerfler, 1983; Riggs and Jones, 1983). Considerable excitement has been generated by the finding that potential methylation sites are often clustered at the 5' regions of genes (Bird et al., 1985). Furthermore, these clusters appear to be protected from methylation when associated with actively expressed genes. These findings have generated a new line of thinking among researchers, namely that genes may be regulated by domains of methylation sites (Jones, 1986). Although the evidence supporting a role for methylation in eukaryotic gene regulation is convincing, it is by no means unequivocal (Bird, 1984). To date, however, determination of the methylation status of specific cytosine residues in DNA has been limited by the experimental tools at hand. Therefore, development of a method that allows for evaluation of the methylation status of all CpG sites within, and in the vicinity of, genes may be necessary to elucidate the exact relationship between DNA methylation and gene expression. The emerging consensus is that DNA methylation is one component of a hierarchy of control mechanisms that regulate eukaryotic gene expression and cellular differentiation. Furthermore, the realization that methylation plays an important role in regulating gene expression during normal cellular differentiation suggests that aberrations in this potential controlling mechanism may be implicated in the abnormal gene expression seen in cancer. Indeed, a large body of experimental evidence demonstrates altered levels and patterns of methylation in tumor cells (Riggs and Jones, 1983; Jones, 1986). The regulatory function of 5-mCyt is most likely exerted via DNA-protein interactions. Two key questions remain unanswered: How does 5-mCyt affect these interactions? More importantly, what are the proteins that modulate DNA methylation during differentiation?

5-Methylcytosine↗
PubMed1998

Rapid, fluorometric DNA determination for chick limb-bud mesenchymal-cell microcultures.

Micromass cultures of chick and mouse limb-bud mesenchymal cells are commonly used for in vitro studies of cellular differentiation. Previously, adaptation of these cultures to 96-well plates facilitated analyses of various aspects of cellular behavior and the effects of different media components in these cultures. These adjustments allowed development of a serum-free medium for chick limb-bud mesenchymal cells and substantially decreased costs associated with media and reagents. Here we report a further development for this model system; a Hoechst 33342-based in situ DNA assay that provides reliable data much more quickly and with considerably less effort than had been feasible in the past. Because it allows quantitation of products of cellular differentiation and DNA in the same cultures, the number of cultures needed to provide the same data is essentially halved and the accuracy of normalized values for quantitative estimates of markers of differentiation is improved. Studies of the effects of retinoic acid on chick limb-bud mesenchymal cells were performed to document the usefulness of this method.

Animals↗
PubMed2003

Interplay between the tumor suppressor p53 and TGF beta signaling shapes embryonic body axes in Xenopus.

The transcription factor p53 has been shown to mediate cellular responses to diverse stresses such as DNA damage. However, the function of p53 in cellular differentiation in response to growth factor stimulations has remained obscure. We present evidence that p53 regulates cellular differentiation by modulating signaling of the TGF beta family of growth factors during early Xenopus embryogenesis. We show that p53 functionally and physically interacts with the activin and bone morphogenetic protein pathways to directly induce the expression of the homeobox genes Xhox3 and Mix.1/2. Furthermore, functional knockdown of p53 in embryos by an antisense morpholino oligonucleotide reveals that p53 is required for the development of dorsal and ventral mesoderm. Our data illustrate a pivotal role of interplay between the p53 and TGF beta pathways in cell fate determination during early vertebrate embryogenesis.

Animals↗
PubMed1989

Effect of docosahexaenoic acid on rate of differentiation of HL-60 human leukemia.

We have utilized an experimental model of cell lipid modification that allows study of the effect of a polyunsaturated fatty acid on the linked processes of cellular differentiation and growth arrest. HL-60 human leukemia cells were grown in media supplemented with 10 microM concentrations of the fatty acid docosahexaenoic acid (22:6) or oleic acid (18:1) or in unsupplemented media. Gas chromatographic analysis of phospholipid extracts from HL-60 cells grown in unmodified or 18:1-supplemented media revealed 39% and 36% 18:1, 13 and 12% polyenoics, and 2 and 3% 22:6, respectively. In contrast, cells from 22:6-supplemented cultures had 22% 18:1, 18% total polyunsaturated fatty acids, and 10% 22:6. Retinoic acid was added to cells grown in the various media, and phorbol ester-induced superoxide generation, nitroblue tetrazolium reduction, and growth arrest were determined as measures of differentiation. Unmodified and 18:1-enriched cells showed inducible oxidative burst activity beginning at 48 h after the addition of retinoic acid and continuing to increase for 5 days. In marked contrast, the 22:6-enriched leukemia cells exhibited an increased oxidative activity as early as 24 h which is equivalent to about one division cycle time. G1/0-specific growth arrest was associated with the oxidative phenotypic differentiation in all three cell types. However, cells enriched with 22:6 demonstrated early growth arrest and differentiation considerably in advance of 18:1-modified or unmodified cells. An effect on the cellular differentiation process could be detected after even a brief 1-h exposure of the cells to 22:6. Therefore, a highly polyunsaturated fatty acid which is actively incorporated into membrane structures appreciably accelerates the differentiation process of this human neoplastic cell.

Cell Cycle↗
PubMed2004

Human cytomegalovirus induces inhibition of macrophage differentiation by binding to human aminopeptidase N/CD13.

Human CMV (HCMV) infection in immunocompromised patients is frequently associated with impaired immunological functions. We have recently found that HCMV inhibits cytokine-induced differentiation of monocytes into macrophages. In this study, we demonstrate that HCMV-induced inhibition of macrophage differentiation was dependent on binding of virus particles to the cell surface molecule CD13/aminopeptidase N, which involved Ca2+ -dependent intracellular signaling pathways. We found that treatment of cells with the CD13-specific mAbs My7 and WM15 inhibited macrophage differentiation, and that My7 and WM15 induced a rise in intracellular Ca2+ in similar ways as HCMV. In contrast, binding of the CD13-specific Ab clone SJ1D1 blocked the ability of HCMV to inhibit macrophage differentiation, and blocked the HCMV-induced intracellular Ca2+ response. In addition, the Ca2+ modulator thapsigargin partially blocked the ability of HCMV to inhibit cellular differentiation. Furthermore, we demonstrate that recombinant viral glycoprotein gB was able to inhibit macrophage differentiation in similar ways as the virus. Thus, these results suggest that binding of HCMV to monocytes induces an intracellular rise of Ca2+, of which one result is a block in the ability of the cells to differentiate into macrophages. These observations suggest an efficient viral strategy to interfere with cellular differentiation pathways, and may also in part explain the generalized immunosuppression that is often observed in HCMV-infected patients.

Antigens, CD↗
PubMed1996

Reduction of LAK-sensitivity and changes in antigen expression on hepatoma cells by sodium butyrate.

We demonstrated that sodium butyrate (SB) induced differentiation of functions in human hepatocellular carcinoma (HCC) cell lines. To investigate relationship between the sensitivity for cellular cytotoxicity and the cellular differentiation of HCC cells, the effect of SB on lymphokine-activated killer (LAK) sensitivity and antigen expression of a human HCC cells were studied. SB induced LAK-resistance of human HCC cell lines, HCC-T and HCC-M, time-dependently. A flowcytometric analysis of cell surface antigens revealed that SB markedly reduced the expression of laminin and fibronectin and increased the expression of liver-specific antigen defined by a mouse monoclonal antibody time-dependently, but did not modify that of major histocompatibility complex antigens, intercellular adhesion molecule (ICAM)-1, or CEA. Leukocyte function-associated antigen (LFA)-3 expression on HCC-T was reduced slightly by SB treatment. LAK sensitivity was inhibited by anti-laminin, but not with anti-beta 2-microglobulin, anti-HLA DR, anti-ICAM-1, anti-fibronectin, or anti-CEA. Anti-LFA-3 reduced LAK sensitivity of HCC-T, but not HCC-M, although the reduction was less than that obtained by anti-laminin treatment. These results provided evidence that SB induced LAK-resistance of human HCC cells according to cellular differentiation and extracellular matrix functionality played an important role in this LAK-mediated cell killing. Moreover, the structure expressed on HCC cells, which contributed to LAK cytolysis, was different for each HCC cell.

Animals↗
PubMed1995

Interrelation of differentiation, proliferation and apoptosis in cancer cells.

Treatment of human leukemia HL-60 cells with ceramide, a breakdown product of sphingomyelin, induced both programmed cell death ("apoptosis"), and cellular differentiation. Apoptosis in response to ceramide occurred in a concentration-dependent manner. Apoptosis induced by ceramide in HL-60 cells requires the presence of c-jun protooncogene. However apoptosis is inhibited by curcumin, a specific inhibitor of c-jun/AP-1. Whereas curcumin restores ability of inhibited cells to grow, it does not affect ceramide-induced differentiation. These results indicate that ceramide controls cell differentiation and proliferation through apoptosis by activating the nuclear transcriptional factor AP-1. Further, AP-1 is apparently more closely related to apoptosis-inducing signal transduction pathway than to the pathway leading to cellular differentiation.

Apoptosis↗
PubMed1998

Differential expression of lactoseries carbohydrate epitopes HNK-1, CD15, and NALA by olfactory receptor neurons in the developing chick.

The formation of the nasal lining with its sensory and its nonsensitive respiratory epithelium requires a spatially ordered pattern of cellular differentiation. Aiming at identifying cell recognition molecules that may be involved in cellular differentiation steps, we applied a panel of antibodies to terminal carbohydrate sequences of the lactoseries on the developing chick olfactory epithelium. This approach is based on the idea that these terminal sugar residues may be involved in certain steps of maturation. Restricted expression of three epitopes NALA, HNK-1, and CD15 was observed in olfactory receptor neurons. The first immature olfactory receptor neurons were observed by day 3 of incubation, expressing the HNK-1 epitope, whereas a total epithelial staining was observed for NALA. By day 9 of incubation high numbers of HNK-1 positive immature olfactory receptor neurons were observed. At the same time mature olfactory receptor neurons showed immunoreactivity for CD15, whereas NALA was still expressed throughout the whole epithelial cell population. However, there was a pronounced staining in the population of mature olfactory receptor neurons. Around hatching only CD15 was detectable in (mature) olfactory receptor neurons, whereas HNK-1 and NALA immunoreactivity have switched to glandular and sustentacular cells respectively. The differentiation-dependent expression patterns of these three cell surface molecules suggest them as suitable markers to explore mechanisms that determine embryonic olfactory receptor neurogenesis.

Animals↗
PubMed1999

Regulation of antioxidant enzyme gene expression in response to oxidative stress and during differentiation of mouse skeletal muscle.

Various properties of skeletal muscle, including high metabolic activity and high levels of heme-containing proteins, render it particularly susceptible to free radical injury. Indeed, cellular injury from reactive oxygen species (ROS) has been implicated in many muscle disorders. Thus muscle cell survival is critically dependent on the ability of the cell to respond to periods of oxidative stress. To investigate this important homeostatic response, we studied the effect of oxidative challenges on the expression of genes encoding the antioxidant enzymes Cu,Zn-superoxide dismutase (CuZnSOD), Mn-superoxide dismutase (MnSOD), glutathione peroxidase (GPx), and catalase (CAT) in myotube cultures. Using Northern blot analysis, we found that treatment with the pro-oxidant paraquat resulted in time- and dose-dependent increases of transcript levels that were greatest for GPx and CAT (approximately 4-5 fold). CuZnSOD and MnSOD transcripts were also increased, albeit more modestly (approximately 2-3 fold). Transcript levels were also induced by treatment of the cells with two other pro-oxidants, menadione and H2O2, and correlated with the level of oxidative injury to the cells, measured as protein carbonyl group formation. Activities of all of the enzymes increased in response to the oxidative challenges, although the magnitudes of the increases were less robust than the increases of the respective transcript levels. In studying the effect of cellular differentiation on antioxidant gene expression and susceptibility to oxidative stress, we found that pro-oxidant treatment resulted in greater oxidative injury to differentiated myotubes than to undifferentiated myoblasts. Furthermore, the increased susceptibility of myotubes correlated with decreased antioxidant defenses-as muscle cells differentiated, both transcript and activity levels of antioxidant enzymes decreased. These data suggest that muscle cells regulate antioxidant defenses in response to oxidative stress and cellular differentiation.

Animals↗
PubMed1999

Granulocytic differentiation of myeloid progenitor cells by p130, the retinoblastoma tumor suppressor homologue.

The retinoblastoma protein (pRB) and the related pocket proteins, p107 and p130, play crucial roles in mammalian cell cycle control. Recent studies indicate that these pocket proteins are also involved in cellular differentiation processes. We demonstrate in this work that the pRB-related p130 selectively accumulates during the in vitro differentiation of the myeloid progenitor cell, 32Dcl3, into granulocyte in response to granulocyte-colony stimulating factor (G-CSF). This G-CSF-dependent granulocytic differentiation is blocked by the adenovirus E1A oncoprotein, which binds to and inactivates the pRB family of pocket proteins including p130. Furthermore, enforced overexpression of p130 but not pRB inhibits the myeloid cell proliferation that is concomitantly associated with granulocytic differentiation morphologically characterized by nuclear segmentation. However, simple G1-cell cycle arrest induced by cytokine deprivation or ectopic overexpression of the p27 cyclin-dependent kinase inhibitor, or inhibition of E2F activities by dominant negative DP-1 is not sufficient to trigger granulocytic differentiation. The differentiation-promoting activity of p130 in myeloid cells requires both the pocket domain and the spacer domain. Our results indicate that the pRB-related p130 plays a critical role in myeloid cell differentiation and suggest that coupling of cell cycle exit with the cellular differentiation program may be specifically achieved by p130.

Adenovirus E1A Proteins↗
PubMed2002

Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system.

BACKGROUND: The Cdx genes are expressed in the colorectal epithelium and are frequently downregulated during tumorigenesis. Overexpression of Cdx genes has been shown previously to result in cellular differentiation. AIM: To study expression of CDX2 in normal and neoplastic human colon using a newly isolated monoclonal antibody. To define expression of CDX1 and CDX2 in an in vitro model system of colorectal tumour progression and to ascertain whether these are subject to regulation during differentiation. METHODS: Normal and neoplastic human colon was immunostained for CDX2. CDX1 and CDX2 expression was assayed in cell lines derived from premalignant colonic adenomas by western blotting. Differentiation was induced by sodium butyrate treatment or post confluent growth, and changes in CDX expression compared with carcinoma cell lines with low levels of CDX expression. RESULTS: CDX2 protein displayed no gradient of expression within the colonic crypt. Cell lines derived from adenomas, with high levels of CDX1 and CDX2, showed no regulation of these proteins when induced to differentiate by butyrate or confluency. CDX expression in these cell lines was independent of their APC or Ras status. CDX1 and CDX2 were expressed at very low levels in some carcinoma cell lines and were modestly upregulated on differentiation but were not restored to levels seen in adenoma cells. CONCLUSION: The lack of significant regulation on cellular differentiation and the absence of a detectable gradient in the crypt implies that CDX2 may confer tissue specificity but may not play the previously suggested role in crypt patterning.

Adenoma↗