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PubMed1989

Differentiation increases type II calmodulin-dependent protein kinase in the neuroblastoma/glioma cell line 108CC15 (NG108-15).

A type II calcium/calmodulin-dependent protein kinase (CaM kinase II) was purified approximately 300-fold from cultured neuroblastoma/glioma (NG108) cell homogenate. The purification of the kinase, which used a combination of differential centrifugation and chromatography on cation-exchange, calmodulin-affinity, and gel-filtration resins, was monitored by the ability of the kinase to phosphorylate the high-molecular-weight microtubule-associated protein 2 (MAP-2). The kinase was compared with authentic CaM kinase II purified from rat brain cytosol. Based upon holoenzyme molecular weight, subunit composition and molecular weight, calcium-dependent calmodulin-binding to subunits, calcium/calmodulin-dependent autophosphorylation of subunits, substrate specificity, apparent km's for ATP and calmodulin, phosphopeptide maps of subunits, time course, and heat lability, the kinase was identified as a type II calcium/calmodulin-dependent protein kinase. When cellular differentiation was induced under specific conditions of cell culture, a significant increase in the apparent activity and amount of the kinase per mg protein was observed relative to control cells. These studies suggest that there is an increase in CaM kinase II expression during cellular differentiation, which may relate to the concurrent development of electrical excitability, synaptogenesis, and elaboration of cytoskeletal elements. Thus, the NG108 cell should provide a useful model to study the physiological functions of CaM kinase II.

Animals↗
PubMed2006

Downregulation of hnRNP C1/C2 by siRNA sensitizes HeLa cells to various stresses.

The heterogeneous nuclear ribonucleoprotein C1/C2 is one of the most abundant proteins in the nucleus, and shown to have roles in cellular differentiation and proliferation through post-transcriptional regulations of certain mRNA species. We studied its role in stress response using siRNA mediated knockdown approach in HeLa cells. Upon transient transfection with plasmid encoding siRNA, the cells showed increased sensitivities to various chemical agents, namely H(2)O(2, )paraquat, camptothecin, ICRF-193 and halogenated deoxyuridines. These results demonstrate that hnRNP C1/C2 is involved in maintenance of cellular homeostasis besides cellular differentiation and proliferation.

Antimetabolites↗
PubMed2003

Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation.

Fracture healing is a specialized post-natal repair process that recapitulates aspects of embryological skeletal development. While many of the molecular mechanisms that control cellular differentiation and growth during embryogenesis recur during fracture healing, these processes take place in a post-natal environment that is unique and distinct from those which exist during embryogenesis. This Prospect Article will highlight a number of central biological processes that are believed to be crucial in the embryonic differentiation and growth of skeletal tissues and review the functional role of these processes during fracture healing. Specific aspects of fracture healing that will be considered in relation to embryological development are: (1) the anatomic structure of the fracture callus as it evolves during healing; (2) the origins of stem cells and morphogenetic signals that facilitate the repair process; (3) the role of the biomechanical environment in controlling cellular differentiation during repair; (4) the role of three key groups of soluble factors, pro-inflammatory cytokines, the TGF-beta superfamily, and angiogenic factors, during repair; and (5) the relationship of the genetic components that control bone mass and remodeling to the mechanisms that control skeletal tissue repair in response to fracture.

Angiogenesis Inducing Agents↗
PubMed2001

Short chain fatty acids differentially modulate cellular phenotype and c-myc protein levels in primary human nonmalignant and malignant colonocytes.

Short chain fatty acids may protect colonic mucosa against neoplastic transformation by modulating colonocyte phenotype, DNA synthesis, and c-myc levels. To test this hypothesis, nonmalignant and malignant human colonocytes were isolated from surgical specimens and treated with 10 mM acetate, propionate, or butyrate. Markers of cellular phenotype, DNA synthesis, and c-myc protein levels were assayed by alkaline phosphatase and dipeptidyl dipeptidase IV activities, [3H]thymidine labeling, and western blotting, respectively. Butyrate, in particular, exerted discordant effects on alkaline phosphatase (P < 0.05), and c-myc levels (P < 0.05, N > or = 6) in nonmalignant and malignant human colonocytes. DPDD was unaffected by any of the short chain fatty acids tested. [3H]Thymidine labeling was differentially stimulated by short chain fatty acids in both cell types and greater DNA synthesis rates were observed in malignant colonocytes (P < 0.005, N = 16). These data suggest that in vitro, butyrate, in particular, may differentially modulate phenotype, DNA synthesis, and c-myc in nonmalignant and malignant human colonocytes.

Aged↗
PubMedDate not supplied

[Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection?].

Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which mediates its actions on vasoconstriction, renin (inhibition) and aldosterone (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1 (often called AT2) receptors. Mainly expressed in the embryon these latter may favor cellular differentiation and recruitment of collateral circulation. Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and therefore the stimulation of both receptor types whereas AT1-receptor antagonists (AT1RA) block only the stimulation of these latter and increase the stimulation of AT2 receptor since they increase the production of All secondarily to the inhibition of the feedback of renin secretion by All. Experimentally ACEI and AT1RA decrease angiogenesis and cellular proliferation and favor cellular differentiation which could explain the protective effect of ACEI against cancer suggested recently in a Scotish study. Despite of their common suppressive effect on angiogenesis AT1RA may better than ACEI protect against ischemic events specially the cerebral ones because they favor the rapid recruitment of collateral circulation. This has been demonstrated for losartan in case of abrupt ligation of the carotid in the gerbil since its previous administration protects against fatal cerebral ischemia whereas its previous administration with enalapril abolishes this protection. These data may explain why, in the CAPP trial, captopril which has prevented more effectively diabetes occurrence could not be proved superior to diuretics and/or betablocker in the prevention of myocardial infarction and specially of strokes for which exist on the contrary a suspicion of a lower protection. Therefore a comparative trial between AT1RA and ACEI in the prevention of stroke recurrence should appear as a priority for Public Health and Pharmaceutical Industry Authorities.

Angiotensin II↗
PubMed1997

Reduction of heat-shock protein-70 after prolonged treatment with retinoids: biological and clinical implications.

Heat shock proteins (HSPs) are a group of highly conserved polypeptides involved in cellular response to heat or other physical or chemical stresses. It has been recently reported that HSPs could play a role in cellular differentiation. In this study we have evaluated, by a cytofluorimetric method, the presence of HSP-70 in HL-60 cells during treatment with all-trans retinoic acid (ATRA), 9-cis retinoic acid (9-cis RA), and 13-cis retinoic acid (13-cis RA). After 1 and 3 days of incubation at 10(-7) M, HSP-70 did not show any variation compared to control; prolonging the exposure, together with the appearance of cellular differentiation along the granulocytic pathway and apoptosis, a progressive decrease of HSP-70 was observed that, after 8 days of treatment, was reduced by 40% with ATRA and by 28% with 9-cis RA compared to untreated samples, while only minimal changes were evident by incubating the cells with 13-cis RA. Reduction of HSP-70 was not associated with decreased protein synthesis, as demonstrated by [3H] leucine incorporation. Double labeling with propidium iodide showed a decrease in HSP-70 in all the phases of the cell cycle concomitant with a reduced percentage of cycling cells in ATRA-treated samples. Dot blot and Northern blot analysis demonstrated no change in HSP-70 mRNA after retinoid treatment, thus suggesting a post-transcriptional regulation of the phenomenon. This reduced production of HSP-70 caused by ATRA and by 9-cis RA, though to a lesser extent, could render the cells more sensitive to cytotoxic agents and could provide the rationale for the efficacy of ATRA + chemotherapy combinations.

Alitretinoin↗
PubMed1980

Ectopic hormone syndromes.

Ectopic hormone production is not always associated with endocrine manifestations and if extensive studies of tumour hormones are made it is found that asymptomatic hormone production is often concomitant with neoplasms. The nature of tumour hormones seems essentially indistinguishable from that of native hormones, although there exists in some cases an abundance of precursor or hormone fragments and unbalanced biosynthesis of subunits. Production of multiple hormones by a tumour is not uncommon. These facts may suggest abnormal gene expression as the basic mechanism responsible for ectopic hormone production. During the process of cellular differentiation, most of the genes are inactivated. Neoplastic transformation may activate repressed genes, thus producing hormones that are not produced by differentiated cells (derepression hypothesis). This hypothesis, however, makes it difficult to explain the higher incidence of ACTH-LPH-producing tumours among APUD tumours. Some investigators have postulated that only APUD tumours elaborate ACTH-LPH or other APUD hormones (neuro-endocrine cell hypothesis). However, there have been reported some definite non-APUD tumours which elaborate ACTH-LPH. These facts can be explained by the stepwise, irreversible repression hypothesis of cellular differentiation. In APUD cells, the gene for ACTH-LPH coding may be repressed at the terminal stage of differentiation and may, therefore, be very easily derepressed by neoplastic transformation. On the other hand, the ACTH-LPH gene may be repressed at a relatively early stage in non-APUD cells and be difficult to reactivate even after neoplastic transformation. Further studies on ectopic hormone producing tumours may clarify the mechanism of ectopic hormone production and yield new insights into the fundamental process of malignant change.

Adrenocorticotropic Hormone↗
PubMed2003

Detection of mutant p53 in hepatocellular cancer from Turkey and its correlation with clinicopathologic parameters.

The samples of hepatocellular carcinoma from Turkey, a country with a high prevalence of hepatitis B virus and hepatitis C virus, but low dietary exposure to aflatoxin B1, were examined in order to detect the frequency of mutant p53 and its association with clinical and pathological data. Fifty-two samples of hepatocellular cancer from the patients who were diagnosed in our clinic were included in this study. The mutant p53 protein was searched for by specific enzyme-linked immunosorbent assay. Of 52 patients with hepatocellular carcinoma, 26 (50%) had the mutant p53. The incidence of p53 mutation in hepatocellular cancer patients with chronic liver disease due to hepatitis B virus infection was significantly higher than in those with chronic liver disease due to alcohol, indicating that not alcohol but hepatitis B virus, in fact induces the mutations in p53 gene. In addition, it has been shown that the p53 mutation was significantly associated with the diameter of tumor nodule and the degree of cellular differentiation in hepatocellular cancer. The p53 mutation rate found in our study is concordant for a geography where hepatitis B virus and hepatitis C virus are common. Hepatitis B virus and possibly hepatitis C virus, but not alcohol, should be responsible, to a degree, for the mutational change in p53 protein in hepatocellular cancer patients with chronic liver disease. The p53 mutation is a late event in hepatocarcinogenesis because it is related with cellular differentiation and tumor diameter. The specific ELISA can be a useful screening test in future studies to select the patients for gene therapy using wild-type p53.

Adolescent↗
PubMed1994

Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation.

The deoxycytidine analog 5-aza-2'-deoxycytidine (5-azadCyd) has been widely used as a DNA methylation inhibitor to experimentally induce gene expression and cellular differentiation. Prior to the availability of mutant mice with altered DNA methyltransferase levels, treatment of cells with drugs has been the only means to experimentally manipulate the level of genomic DNA methylation in mammalian cells. Substitution of DNA with 5-azadCyd leads to covalent trapping of the enzyme, thereby depleting the cells of enzyme activity and resulting in DNA demethylation. 5-AzadCyd or 5-azacytidine treatment causes multiple changes in treated cells, including activation of silent genes, decondensation of chromatin, and induction of cellular differentiation, all of which are believed to be consequences of drug-induced demethylation. 5-AzadCyd is highly toxic in cultured cells and animals and is utilized as a potent antitumor agent for treatment of certain human cancers. It has been postulated that the toxicity of the drug in mammalian cells is also due to its inhibition of DNA methylation. The chemistry of the methylation reaction is consistent, however, with an alternative mechanism: the cytotoxic effect of 5-azadCyd may be directly mediated through the covalent binding of DNA methyltransferase to 5-azadCyd-substituted DNA. We have tested this possibility by using embryonic stem cells and mice with reduced levels of DNA methyltransferase due to a targeted mutation of the gene. When exposed to 5-azadCyd mutant embryonic stem cells or embryos were significantly more resistant to the toxic effects of the drug than wild-type cells and embryos, respectively. These results strongly suggest that the cellular DNA methyltransferase itself, rather than the secondary demethylation of genomic DNA, is the primary mediator of 5-azadCyd cytotoxicity. In light of our results, some conclusions from previous studies using 5-azadCyd in order to experimentally manipulate cellular methylation levels may have to be reassessed. Also, our data make clear predictions for cancer treatment: tumor cells with elevated DNA methyltransferase levels would be expected to be susceptible to treatment with 5-azadCyd, whereas tumors with reduced levels of the enzyme would be resistant.

Animals↗
PubMed2004

Recovery from welding-fume-exposure-induced lung fibrosis and pulmonary function changes in sprague dawley rats.

Welder's pneumoconiosis has generally been determined as benign based on the absence of pulmonary function abnormalities in welders with marked radiographic abnormalities. Yet, there have also been several reports on welders with respiratory symptoms, indicating lung function impairment, X-ray abnormalities, and extensive fibrosis. Accordingly, this study attempted to investigate the inflammatory responses and pulmonary function changes in rats during a 60-day welding-fume-inhalation exposure period to elucidate the process of fibrosis. The rats were exposed to manual metal-arc stainless-steel welding fumes (MMA-SS) with total suspended particulate concentrations of 64.8 +/- 0.9 (low dose) and 107.8 +/- 2.6 mg/m3 (high dose) for 2 h per day in an inhalation chamber for 60 days. Animals were sacrificed after the initial 2-h exposure and after 15, 30, and 60 days, and the pulmonary function was also measured every week after the daily exposure. Elevated cellular differential counts were also measured in the acellular bronchoalveolar lavage fluid of the rats exposed to the MMA-SS fumes for 60 days. Among the pulmonary function test parameters, only the tidal volume showed a statistically significant and dose-dependent decrease after 35 to 60 days of MMA-SS welding-fume exposure. When the rats exposed to the welding fumes were left for 60 days to recover their lung function and cellular differentiation, recovery was observed in both the high and low-dose rats exposed up to 30 days, resulting in the disappearance of inflammatory cells and restoration of the tidal volume. The rats exposed for 60 days at the low dose also recovered from the inflammation and tidal volume loss, yet the rats exposed for 60 days at the high dose did not fully recover even after a 60-day recovery period. Therefore, when taken together, the results of the current study suggest that a decrease in the tidal volume could be used as an early indicator of pulmonary fibrosis induced by welding-fume exposure in Sprague Dawley rats, and fibrosis would seem to be preventable if the exposure is short-term and moderate.

Animals↗
PubMed2007

Generalized, switch-like competitive heterodimerization networks.

High-dimensional switches have been proposed as a way to model cellular differentiation, particularly in the context of basic Helix-Loop-Helix (bHLH) competitive heterodimerization networks. A previous study derived a simple rule showing how many elements can be co-expressed, depending on the rate of competition within the network. A limitation to that rule, however, is that many biochemical parameters were considered to be identical. Here, we derive a generalized rule. This in turns allows one to study more ways in which these networks could be regulated, linking intrinsic cellular differentiation determinants to extracellular cues.

Basic Helix-Loop-Helix Proteins↗
PubMed1993

[Immunohistological investigation of the histological origin and differentiation of pleomorphic adenoma of the parotid gland].

Immunohistological expressions of the cytokeratin (CK) subclass, vimentin, glial fibral antigen protein (GFAP), alpha-smooth muscle actin, and S-100 protein were investigated in pleomorphic adenoma of the parotid gland. In addition, the correlation between immunohistological findings in the normal parotid gland and those in pleomorphic adenoma was examined. Vimentin, S-100 protein, and GFAP, which were not detected in the normal parotid gland, were observed in pleomorphic adenoma. Only CK-1, which was not detected in the normal parotid gland, was expressed intensely in squamous metaplastic lesions of pleomorphic adenoma. All other CK detected in pleomorphic adenoma were also expressed in the normal parotid gland. Therefore, the expression of vimentin, S-100 protein, GFAP, and CK-1 in pleomorphic adenoma is related to oncogenesis. Since most types of CK expression were observed in solid pleomorphic adenoma lesions and all types of CK expression detected in other lesions were included, cellular differentiation between solid and nonsolid lesions was elucidated. According to the pattern of CK subclass expression, the following sequence of differentiation was suggested; solid lesion-->myxoid lesion-->chondroid lesion, solid lesion-->tubular lesion, solid lesion-->myoepithelioid lesion, and solid lesion-->squamous metaplastic lesion. In normal parotid glands, satellite cells around the ductal cells showed all types of CK subclass expression detected in myoepithelial cells, acinus cells, and ductal cells. Since the types and patterns of CK expression in solid lesions of pleomorphic adenoma are the same as those in satellite cells in the normal parotid gland, pleomorphic adenoma seems to originate from satellite cells. If satellite cells in the normal parotid gland are considered to be so-called reserve cells in the bicellular theory, the origin and cellular differentiation of pleomorphic adenoma can be explained in relation to CK subclass expression.

Actins↗
PubMed1999

Glycosylphosphatidylinositol-anchored cell-surface proteins from Arabidopsis.

Remodeling of the plant cell surface occurs during the establishment of cell polarity, cellular differentiation, and organ development. This report demonstrates the existence of multiple glycosylphosphatidylinositol (GPI)-anchored proteins in the model plant Arabidopsis. Using two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), we also show that GPI-anchored proteins are a relatively abundant class of protein and that they are present at the plant plasma membrane. Furthermore, some of these proteins are released into the extracellular matrix. At least one of these is an arabinogalactan protein (AGP), a class of proteins known to be associated with cellular differentiation. Analysis of the amino acid sequences of two novel AGP-like proteins from Arabidopsis predicts that these proteins contain consensus signals for GPI-anchor addition. These findings support a model where GPI-anchored proteins are involved in the generation of specialized cell surfaces and extracellular signaling molecules.

Amino Acid Sequence↗
PubMed1990

[The value of surgical staging in the early stages of ovarian carcinoma].

The value of surgery in early ovarian cancer was assessed in a retrospective analysis of prognostic factors in all 222 patients with primary stage I epithelial ovarian carcinoma treated in this department between 1975 and 1987. Only cellular differentiation grade (p less than 0.03) and surgical procedure - total abdominal hysterectomy, bilateral salpingo-oophorectomy +/- omentectomy vs. unilateral salpingo-oophorectomy - (p less than 0.02) were of significant influence on estimated survival (Cox model). All other factors (age, FIGO stage, integrity of the capsule, uni-vs. bilaterality, histology) were of no prognostic importance. Unilateral salpingo-oophorectomy without any additional staging reduces the 5-year survival probability (62% vs. 84%). Future prospective studies on adjuvant therapy must be based on exact staging during surgical management before randomisation. Determination of cellular differentiation is also essential.

Adult↗
PubMed1999

Pyrolysis mass spectrometry analysis of free-living and symbiotic cyanobacteria.

The potential of pyrolysis mass spectrometry to distinguish closely related cyanobacterial strains was assessed by using the technique to compare symbiotic cyanobacteria isolated from the hornwort Phaeoceros laevis and free-living cyanobacterial strains at the same field site. The same strains had previously been compared using polymerase chain reaction-based DNA fingerprinting techniques (West & Adams 1997, Appl. Environ. Microbiol. 63: 4479-4484). Many of the strains were grouped identically by the two techniques, although there were some differences, possibly resulting from the ability of these cyanobacteria to develop a range of specialised cell types having different chemical compositions to the vegetative cells. Although growth conditions were chosen to suppress cellular differentiation, this may not always have been completely successful. With careful control of growth conditions pyrolysis mass spectrometry has considerable potential as an additional tool for the phenetic comparison of cyanobacterial strains. It has the advantage that analysis is directly derived from whole cells, and hence is simpler and cheaper than DNA-based methods, although it does require the growth of axenic strains. The technique may be particularly useful in the study of some of the more cryptic unicellular and non-heterocystous filamentous cyanobacterial groups, in which the lack of cellular differentiation should minimise any variability in the chemical composition of cells.

Bacterial Typing Techniques↗
PubMed1998

Biological effects of inhibitors of S-adenosylhomocysteine hydrolase.

S-Adenosylhomocysteine (AdoHcy), formed after the donation of the methyl group of S-adenosylmethionine to a methyl acceptor, is hydrolyzed to adenosine and homocysteine by AdoHcy hydrolase physiologically. The administration of the inhibitors of AdoHcy hydrolase to cells or animals normally results in an accumulation of cellular AdoHcy higher than those found in controls, which is often accompanied by a simultaneous rise in S-adenosylmethionine because of the feedback inhibition by AdoHcy on most methylation reactions. AdoHcy hydrolase has become a tantalizing pharmacological target for inhibition since its blockade can affect cellular methylation of phospholipids, proteins, small molecules, DNA, and RNA. Indeed, all of these different methylation reactions have been found to be inhibitable by the nucleoside inhibitors/substrates of AdoHcy hydrolase. Among the interesting effects are the activation of genes, induction of cellular differentiation, increased expression of transcription factors, and sometimes the repression of genes. Furthermore, some of the nucleosides show remarkable antiviral activities in vitro and in vivo. However, the mode of action of the inhibitors appears complex. Although the inhibition of methylation might account for some of the biological effects, the ability of some of the nucleoside inhibitors to undergo metabolic phosphorylation to nucleotides may account for part of their biological activities. The defining mode of action responsible for their biological effects still awaits biochemical elaboration, especially regarding their antiviral effects, induction of genes, or cellular differentiation.

Adenosylhomocysteinase↗
PubMed2002

Phenotype of Per1- and Per2-expressing neurons in the suprachiasmatic nucleus of a diurnal rodent (Arvicanthis ansorgei): comparison with a nocturnal species, the rat.

In mammals, the suprachiasmatic nuclei (SCN) are the site of the master circadian pacemaker whose molecular core mechanism is based on interlocking transcriptional/translational feedback loops involving clock genes. Among clock genes, Per1 and Per2 are important for both the maintenance of circadian rhythmicity and entrainment to light cues. Several circadian rhythms (e.g., locomotor activity) present opposite patterns in diurnal and nocturnal species. To test whether a differential cellular expression of clock genes in the SCN could constitute the neural substrate leading to diurnal or nocturnal behavior, we identified, by single or double non-radioactive hybridizations, the phenotype of neurons expressing Per1 and Per2 during the day in a diurnal species, Arvicanthis ansorgei, and in a nocturnal species, the rat (Rattus norvegicus). We show that in both species, expression of Per1 and Per2 is mostly restricted to the dorsomedial part of the SCN, often coexpressed with arginine vasopressin (AVP). A few vasoactive intestinal polypeptide (VIP) neurons were also shown to express Per1 and Per2. This differential expression of Per1 and Per2 in AVP and VIP neurons is more distinct in A. ansorgei than in the rat. Thus, our data suggest a major role for the dorsomedial part of the SCN in the maintenance of circadian rhythmicity. Furthermore, the similar diurnal pattern of Per1 and Per2 expression in diurnal and nocturnal rodents suggests that the circadian organization of locomotor activity rhythms probably relies on differential cellular integration mechanisms downstream of the clock.

Animals↗
PubMed1984

RNA tumor viruses, DNA tumor viruses and developmental switches: a unifying hypothesis.

It is hypothesized that oncogenic viruses (both RNA and DNA tumor viruses) use cellular differentiation switches as part of their mechanism for viral replication. Chemical or radiation-induced carcinogenesis is the result of mutations which also affect these differentiation switches and their cellular controls. A transformed cell is characterized by the uncontrolled and inappropriate expression of embryonic (developmental) sequences. Many of the oncogenic viruses, both RNA and DNA, are lineage- and stage-specific in the cells they can productively infect, in keeping with their means of replication. The interaction between virus and host cellular controls determines whether recognizable neoplasia will result from viral infection.

Animals↗