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PubMed2002

Taming the fierce roller: an "enhanced" understanding of cellular differentiation in Volvox.

Few organisms offer a better opportunity to explore the mechanisms of cellular differentiation, and their origins, than Volvox. Volvox consists of just two cell types, germ and soma, and is the most complex member of a family of green algae that includes unicellular and multicellular relatives. At the heart of the cell-fate determination program of Volvox carteri is the regA gene, which encodes a putative transcriptional repressor that prevents somatic cells from expressing reproductive functions. Stark et al. have dissected the regA gene to determine how its expression is restricted to somatic cells. Their results suggest that regA expression is controlled by multiple enhancers, the most important of which prevents transcription in reproductive cells. While these findings shed light on Volvox development, they also raise a new set of questions about the mechanisms that control the germ-soma dichotomy in this organism.

Algal Proteins↗
PubMed2004

Cellular differentiation and the NtcA transcription factor in filamentous cyanobacteria.

Some filamentous cyanobacteria can undergo a variety of cellular differentiation processes that permit their better adaptation to certain environmental conditions. These processes include the differentiation of hormogonia, short filaments aimed at the dispersal of the organism in the environment, of akinetes, cells resistant to various stress conditions, and of heterocysts, cells specialized in the fixation of atmospheric nitrogen in oxic environments. NtcA is a transcriptional regulator that operates global nitrogen control in cyanobacteria by activating (and in some cases repressing) many genes involved in nitrogen assimilation. NtcA is required for the triggering of heterocyst differentiation and for subsequent steps of its development and function. This requirement is based on the role of NtcA as an activator of the expression of hetR and other multiple genes at specific steps of the differentiation process. The products of these genes effect development as well as the distinct metabolism of the mature heterocyst. The different features found in the NtcA-dependent promoters, together with the cellular level of active NtcA protein, should have a role in the determination of the hierarchy of gene activation during the process of heterocyst differentiation.

Adaptation, Physiological↗
PubMed2005

Differential expression of endogenous sialidases of human monocytes during cellular differentiation into macrophages.

Sialidases are enzymes that influence cellular activity by removing terminal sialic acid from glycolipids and glycoproteins. Four genetically distinct sialidases have been identified in mammalian cells. In this study, we demonstrate that three of these sialidases, lysosomal Neu1 and Neu4 and plasma membrane-associated Neu3, are expressed in human monocytes. When measured using the artificial substrate 2'-(4-methylumbelliferyl)-alpha-d-N-acetylneuraminic acid (4-MU-NANA), sialidase activity of monocytes increased up to 14-fold per milligram of total protein after cells had differentiated into macrophages. In these same cells, the specific activity of other cellular proteins (e.g. beta-galactosidase, cathepsin A and alkaline phosphatase) increased only two- to fourfold during differentiation of monocytes. Sialidase activity measured with 4-MU-NANA resulted from increased expression of Neu1, as removal of Neu1 from the cell lysate by immunoprecipitation eliminated more than 99% of detectable sialidase activity. When exogenous mixed bovine gangliosides were used as substrates, there was a twofold increase in sialidase activity per milligram of total protein in monocyte-derived macrophages in comparison to monocytes. The increased activity measured with mixed gangliosides was not affected by removal of Neu1, suggesting that the expression of a sialidase other than Neu1 was present in macrophages. The amount of Neu1 and Neu3 RNAs detected by real time RT-PCR increased as monocytes differentiated into macrophages, whereas the amount of Neu4 RNA decreased. No RNA encoding the cytosolic sialidase (Neu2) was detected in monocytes or macrophages. Western blot analysis using specific antibodies showed that the amount of Neu1 and Neu3 proteins increased during monocyte differentiation. Thus, the differentiation of monocytes into macrophages is associated with regulation of the expression of at least three distinct cellular sialidases, with specific up-regulation of the enzyme activity of only Neu1.

Animals↗
PubMed2002

Relationship between degree of cellular differentiation in colorectal cancer and topographical distribution.

OBJECTIVES: To demonstrate the relationship between degree of cellular differentiation in colorectal cancer and topographical distribution in 215 patients diagnosed with colorectal cancer from 1997 to 2000. MATERIAL AND METHODS: 215 patients (129 men and 86 women) were studied prospectively with a mean age of 64 years (range: 23-84 years). In all patients we performed a full colonoscopy with several biopsies (in patients with colon stenosis we used barium enema), radiographic studies (CT, abdominal ultrasounds), and laboratory tests for serum tumour markers (CEA, Ca 19-9, alpha-fetoprotein). The topographic location of colorectal cancer was: rectum 35%, sigmoid colon 31%, descending colon 10%, transverse colon 6%, ascending colon 9%, caecum 5%, and we included anorectal cancer 4%. RESULTS: According to histological differentiation we found: A) well-differentiated tumours 101/215 (47%); B) moderately-differentiated tumours 98/215 (45.5%), and C) poorly-differentiated tumours 16/215 (7.5%). We found no significant association among histological differentiation, topographic location, stage according to the Astler-Coller classification, sex or age (p = ns). The prevalence of well-differentiated tumours in men was 49% and 43% in women; of moderately-differentiated cancers in men was 43%, and 49% in women; for poorly-differentiated tumours in men was 7.5%, and 7.2% in women. Regarding tumour location, 165 cancers were found in the left colon: 80 were well differentiated, 77 moderately differentiated and 8 poorly differentiated. In the transverse colon we found 12 tumours: 7 well differentiated, 3 moderately differentiated and 2 poorly differentiated. 30 cancers were localized in the right colon: 11 well differentiated, 15 moderately differentiated and 4 poorly differentiated. In the anorectum 8 tumours were found: 3 well differentiated, 3 moderately differentiated and 2 poorly differentiated. According to staging classification, well differentiated tumours (101/215) were more common in Dukes' C2 (20.7%) and B1 (32.6%), moderately differentiated cancers (98/215) were in B1 (28.5%) and C2 (20.4%), and poorly differentiated tumours (16) were more common in Dukes' C2 (25%), without differences among other stages (p = ns). CONCLUSIONS: According to our results we have found that histological differentiation of colorectal cancer has no association with topographic location, and it is independent of sex or age. We have not found any relationship either between histological differentiation and stage in the Astler-Coller classification, but well differentiated cancers were more common at any location, age or sex.

Adult↗
PubMed1988

Influence of cellular differentiation on repair of ultraviolet-induced DNA damage in murine proadipocytes.

The effects of cellular differentiation on the repair of DNA damage induced by uv radiation were investigated in the murine 3T3-T proadipocyte cell culture system. Upon exposure to human plasma, actively cycling 3T3-T cells (stem cells) undergo growth arrest, which is followed by terminal differentiation into lipid-laden adipocytes. In response to uv irradiation, the level of unscheduled DNA synthesis is significantly lower in adipocytes as compared to stem cells. The alkaline elution assay was used to monitor the appearance of repair-induced strand breaks in 3T3-T cells after uv irradiation. DNA strand breaks were detected in stem cells by 4 min post-uv with essentially no further increase after 8 min. When terminally differentiated adipocytes were irradiated and allowed to repair, however, more strand breaks were present at 4 min and, in marked contrast to stem cells, continued to accumulate in adipocytes for at least 16 min post-uv. Inhibition of repair-replication with hydroxyurea and cytosine arabinoside significantly increased accumulation of repair-induced strand breaks in stem cells, yet had little effect on this accumulation in adipocytes. For stem cells and adipocytes, incision activity was linear out to at least 10 Jm-2 without saturation. These data suggested that 3T3-T cell differentiation is accompanied by a defect in some postincision process of the excision-repair pathway.

Adipose Tissue↗
PubMed1998

Cellular differentiation in the leaf.

The past year has seen significant advances in our understanding of the mechanisms that regulate cellular differentiation in the leaf. It has been suggested that a common developmental pathway involving MYB-like transcription factors is responsible for distinguishing between cellular identities in the epidermis and that nuclear-cytoplasmic partitioning of the GLABRA2 homeodomain protein plays a role in determining trichome cell fate. With respect to the differentiation of subepidermal cell types, molecular links have been made between auxin physiology and vascular development, and between plastid function and photosynthetic cell type development.

Cell Differentiation↗
PubMed1998

Cellular differentiation and I-FABP protein expression modulate fatty acid uptake and diffusion.

The effect of cellular differentiation on fatty acid uptake and intracellular diffusion was examined in transfected pluripotent mouse embryonic stem (ES) cells stably expressing intestinal fatty acid binding protein (I-FABP). Control ES cells, whether differentiated or undifferentiated, did not express I-FABP. The initial rate and maximal uptake of the fluorescent fatty acid, 12-(N-methyl)-N-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-octadec anoic acid (NBD-stearic acid), was measured in single cells by kinetic digital fluorescence imaging. I-FABP expression in undifferentiated ES cells increased the initial rate and maximal uptake of NBD-stearic acid 1.7- and 1.6-fold, respectively, as well as increased its effective intracellular diffusion constant (Deff) 1.8-fold as measured by the fluorescence recovery after photobleaching technique. In contrast, ES cell differentiation decreased I-FABP expression up to 3-fold and decreased the NBD-stearic acid initial rate of uptake, maximal uptake, and Deff by 10-, 4.7-, and 2-fold, respectively. There were no significant differences in these parameters between the differentiated control and differentiated I-FABP-expressing ES cell lines. In summary, differentiation and expression of I-FABP oppositely modulated NBD-stearic acid uptake parameters and intracellular diffusion in ES cells.

4-Chloro-7-nitrobenzofurazan↗
PubMed1985

Cytochemistry of acute promyelocytic leukemia (M3): leukemic promyelocytes exhibit heterogeneous patterns in cellular differentiation.

Cytochemical investigation of leukemic promyelocytes from 25 cases of acute promyelocytic leukemia (M3) disclosed two major cellular differentiation categories: (1) the pure neutrophilic (N) type (16 cases) with strong myeloperoxidase (MPO) and naphthol-ASD chloroacetate esterase (Es-chl), but lacking the monocytic enzyme NaF-sensitive alpha-naphthyl butyrate esterase (Es-b), and (2) the mixed neutrophilic/monocytoid (N/M) type (seven cases) with strong Es-b as well as strong MPO, all cases exhibiting Es-dual (Es-b + Es-chl) positive cells. Two more cases with unusual phenotypes were noted: one with intense lysozyme activity but without Es-b and the other with toluidine blue-methachromasia and negative MPO. Promyelocytes from the control group, consisting of nine cases of t(8;21) M2 AML and ten cases with normal bone marrow, lacked such cytochemical heterogeneity. HL-60, an M3 cell line that can be induced to differentiate toward monocytic lineage in vitro, was almost negative for Es-b in the uninduced condition. Cytogenetically, eight cases of N type and five of N/M type had the t(15;17) abnormality. Thus at least two differentiation patterns were observed in M3 leukemia with fidelity (N type) and infidelity (N/M type) for normal granulocytic differentiation. In this series, there was no statistically significant difference in clinical features (remission rate and survival) between the two types. Our study suggests that the development of M3 leukemia is not exclusively restricted to the neutrophilic pathway, but more heterogeneously related to myelomonocytic differentiation.

Adolescent↗
PubMed2000

Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1.

Quinidine inhibits proliferation and promotes cellular differentiation in human breast tumor epithelial cells. Previously we showed quinidine arrested MCF-7 cells in G(1) phase of the cell cycle and led to a G(1) to G(0) transition followed by apoptotic cell death. The present experiments demonstrated that MCF-7, MCF-7ras, T47D, MDA-MB-231, and MDA-MB-435 cells transiently differentiate before undergoing apoptosis in response to quinidine. The cells accumulated lipid droplets, and the cytokeratin 18 cytoskeleton was reorganized. Hyperacetylated histone H4 appeared within 2 h of the addition of quinidine to the medium, and levels were maximal by 24 h. Quinidine-treated MCF-7 cells showed elevated p21(WAF1), hypophosphorylation and suppression of retinoblastoma protein, and down-regulation of cyclin D1, similar to the cell cycle response observed with cells induced to differentiate by histone deacetylase inhibitors, trichostatin A, and trapoxin. Quinidine did not show evidence for direct inhibition of histone deacetylase enzymatic activity in vitro. HDAC1 was undetectable in MCF-7 cells 30 min after addition of quinidine to the growth medium. The proteasome inhibitors MG-132 and lactacystin completely protected HDAC1 from the action of quinidine. We conclude that quinidine is a breast tumor cell differentiating agent that causes the loss of HDAC1 via a proteasomal sensitive mechanism.

Acetylation↗
PubMed2001

SPO14 separation-of-function mutations define unique roles for phospholipase D in secretion and cellular differentiation in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, phospholipase D (PLD), encoded by the SPO14 gene, catalyzes the hydrolysis of phosphatidylcholine, producing choline and phosphatidic acid. SPO14 is essential for cellular differentiation during meiosis and is required for Golgi function when the normal secretory apparatus is perturbed (Sec14-independent secretion). We isolated specific alleles of SPO14 that support Sec14-independent secretion but not sporulation. Identification of these separation-of-function alleles indicates that the role of PLD in these two physiological processes is distinct. Analyses of the mutants reveal that the corresponding proteins are stable, phosphorylated, catalytically active in vitro, and can localize properly within the cell during meiosis. Surprisingly, the separation-of-function mutations map to the conserved catalytic region of the PLD protein. Choline and phosphatidic acid molecular species profiles during Sec14-independent secretion and meiosis reveal that while strains harboring one of these alleles, spo14S-11, hydrolyze phosphatidylcholine in Sec14-independent secretion, they fail to do so during sporulation or normal vegetative growth. These results demonstrate that Spo14 PLD catalytic activity and cellular function can be differentially regulated at the level of phosphatidylcholine hydrolysis.

Alleles↗
PubMed1996

Isolation and characterization of a 14.5-kDa trichloroacetic-acid-soluble translational inhibitor protein from human monocytes that is upregulated upon cellular differentiation.

A trichloroacetic-acid-soluble 14.5-kDa protein (p14.5) has been isolated from human mononuclear phagocytes (MNP) by a combination of trichloroacetic acid extraction, preparative electrophoresis and hydrophobic affinity chromatography; five tryptic peptides were subjected to protein sequencing. The full-length cDNA of the protein was cloned and sequenced from a lambda gt11 human liver library. The cDNA showed a remarkable similarity to a rat protein preferentially expressed in hepatocytes and renal tubular epithelial cells. The encoded protein is 137 amino acids long and similar to members of a new hypothetical family of small proteins with presently unknown function, named YER057c/YJGF. Human recombinant p14.5 inhibits in vitro protein synthesis in a rabbit reticulocyte lysate system. Unlike other inhibitors of protein synthesis, p14.5 is not phosphorylated despite the presence of putative phosphorylation sites. The p14.5 mRNA is weakly expressed in freshly isolated monocytes but is significantly upregulated when these monocytes are subjected to differentiation. This is also reflected by a differentiation-dependent increase in the protein concentration as demonstrated by immunoblots from cytosolic fractions and fluorescence-activated flow cytometry of permeabilized cells. A differentiation-dependent mRNA and protein expression of p14.5 is further suggested by the observation of a low expression in a variety of liver and kidney tumor cells and a high expression in fully differentiated cells as assessed by immunohistochemistry and northern blots. The highest mRNA expression was found in hepatocytes and renal distal tubular epithelial cells and only weak expression was found in other human tissues as evaluated by northern blot analysis. The preferential localization of the immunoreaction product seemed to be cytoplasmatic but, in less differentiated cells, nuclear labeling was occasionally visible. Immunoblotting of subcellular fractions confirmed these data. The high degree of evolutionary conservation of p14.5, the considerable upregulation during cellular differentiation and its potential role as a translational inhibitor may reflect an involvement in basic cellular mechanisms, e.g. a differentiation-dependent regulation of protein synthesis in hepatocytes, renal tubular epithelial cells, smooth muscle cells and MNP.

Amino Acid Sequence↗
PubMed1994

Sphinganine potentiation of cellular differentiation induced by various anti-leukemia drugs in human leukemia cell line HL-60.

A slight induction of cellular differentiation (myelocytes and granulocytes) of HL-60 cells occurred after treatment with anti-tumor agents etoposide (VP-16), mitoxantrone (MXT), mitomycin C (MMC), actinomycin D (Act-D) or novobiocin (NOVO). Addition of sphinganine (SP), an inhibitor of protein kinase C (PKC) enhanced (2-3 fold) the VP-16, MXT, MMC or Act-D-induced differentiation but not the NOVO-induced differentiation. No induction of differentiation was observed with 5-fluorouracil (5-FU) in the absence or presence of SP. The addition of SP in the fresh medium after the removal of VP-16, MXT, or MMC (0.5 h treatment) enhanced the induction of differentiation. In contrast, SP post-treatment did not have any effect on enhancing the differentiation which was induced by Act-D short exposure (0.5 h). In an attempt to characterize the biochemical requirements for potentiation of VP-16-induced differentiation, we examined the effects of calcium depletion using calcium chelator ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) or calcium channel blocker verapamil. Potentiation of VP-16-induced differentiation by SP was not observed in EGTA- or verapamil-treated cells. Calcium supplementation to the cells during the treatment with EGTA restored the SP-potentiation of VP-16-induced differentiation. Our results also showed that the induction of differentiation was accompanied by a decrease in PKC activity (70% of the control). PKC activity decreased to a greater extent (50% of control) in SP potentiation of differentiation induction. Our results suggested that calcium-dependent biological action of antitumor agents and the inhibition of PKC activity are required for SP-potentiation of differentiation induction.

Antineoplastic Agents↗
PubMed1985

Cellular differentiation of epithelioid sarcoma. An electron-microscopic, enzyme-histochemical, and immunohistochemical study.

For the purpose of clarifying cellular differentiation of epithelioid sarcoma, studies based on various methods were performed. Enzyme histochemical studies showed that epithelioid sarcoma tumor cells have characteristics intermediate between epithelial cells and the large plump cells of synovial sarcoma-incomplete epithelial differentiation. For alkaline phosphatase and adenosine triphosphatase particularly, positive cells and negative cells coexisted, as in the large plump cells of synovial sarcoma. Immunohistochemical studies for alpha 1-antitrypsin, alpha 1-antichymotrypsin, vimentin, and keratin also showed that epithelioid sarcoma tumor cells are very similar to the large plump cells of synovial sarcoma and have incomplete epithelial differentiation. For example, the examinations of serial sections and double staining methods revealed that keratin-positive cells are always vimentin-positive in epithelioid sarcoma and in the monophasic area of synovial sarcoma. Electron-microscopically, bundles of intermediate filaments and filopodia toward the intercellular lumen were observed, as in the monophasic area of synovial sarcoma. The results of enzyme-histochemical and immunohistochemical studies of non-neoplastic synovial lining cells, performed here for the first time, are also discussed.

Adenosine Triphosphatases↗
PubMed2005

Role of the retinoblastoma tumor suppressor protein in cellular differentiation.

The retinoblastoma protein (pRb105) is a true tumor suppressor as deregulation of the Rb pathway by either mutation of pRb105 itself or other proteins in the pathway, such as p16INK4a, occur in most cancers. This prototypical family member, along with the related p107 and p130, are involved in the control of cell cycle regulation, but pRb105 has also been shown to be involved in tissue development and differentiation. This prospective will discuss the increasing evidence for a role of pRb105 in cellular differentiation and the fact that various cancers, which contain mutant pRb105, or mutations in proteins in the pRb105 pathway, are perhaps a result of deregulation of differentiation.

Animals↗
PubMedDate not supplied

Regulation of cellular differentiation and apoptosis by fatty acids and their metabolites.

We have reviewed the literature regarding the effects of fatty acids and their metabolites on cellular differentiation and apoptosis. Results obtained in different studies have been variable, but some generalizations can be made. Differentiation was increased by incubation of cells with arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), or leukotriene D4 (LTD4). Effects of these agents on differentiation could be magnified with the simultaneous addition of other differentiation-inducing agents like dimethylsulfoxide or retinoic acid. AA and gamma-linolenic acid increased apoptosis while the effects of n-3 fatty acids (EPA and DHA) and of eicosanoids varied from stimulation to inhibition. These inconsistencies are attributed to the differences in methods used to evaluate differentiation and apoptosis, concentrations of fatty acids and serum, exposure time and the cell models used. Studies using the physiological concentrations of the fatty acids and standardized experimental conditions need to be conducted to establish effects of fatty acids and their metabolites on these cellular processes.

Animals↗
PubMed1981

Cellular differentiation and neoplasia: characterization of subpopulations of cells that have neoplasia-related growth properties in Syrian hamster embryo cell cultures.

Cellular subpopulations having two of the growth properties of neoplastically transformed cells--lack of postconfluence inhibition of cell division (CI-) and anchorage independence of growth (AD-)--were found in cell cultures established from 10- to 13-day-old Syrian hamster embryos. The subpopulations having these properties decrease with increasing gestation period of the embryo as well as with continuing passage in vitro. The decrease in these subpopulations was also observed when they were cultured on a lethally irradiated confluent monolayer of contact-inhibited cells (cell mat), a selection condition for CI- cells. Therefore, negative selection cannot be the explanation for the loss of CI- cells in the population, leaving two other possibilities: either the loss of proliferative capacity of the CI- cells or the acquisition of sensitivity to postconfluence inhibition of cell division (CI+) of this subpopulation on in vitro culture or in vivo growth. The CI- subpopulations were isolated clonally from cell mats and were cultured continuously on both cell mats or plastic dishes. The results indicate that these cells did not lose proliferative capacity but acquired the contact-inhibited phenotype. This result, together with the fact that embryonic development in vivo also decreases CI/AD-subpopulations, suggests that the disappearance of these subpopulations is due to cellular differentiation of the CI-/AD- cells to become CI+/AD+ cells.

Age Factors↗
PubMed1989

Use of cultured embryonic chicken osteoblasts as a model of cellular differentiation and bone mineralization.

When chicken embryonic progenitor cells were selected and grown in culture as previously described, by 30 days cellular differentiation could be demonstrated by expression of in vivo levels of osteocalcin, alkaline phosphatase (APase), type I collagen and phosphoproteins (PP). Ultrastructural analysis revealed that the cultures were similar morphologically to young osteoid in vivo with structural features including well-developed, orthogonally arranged collagen fibrils with 64-70 nm periodicity and electron opaque areas consisting of very poorly crystalline hydroxyapatite. Analysis of collagen synthesis versus collagen accumulation in the matrix indicated a temporal inconsistency between the time of synthesis and accumulation, suggesting that accumulation was largely controlled at the level of fibril formation. Analysis of PP accumulation demonstrated a 10-fold increase in total phosphoamino acid content over the 30 day time course. PP synthesis analyzed by [3H]-Ser(P) and [14C]-Thr(P) incorporation showed an induction similar to that seen for APase. Experiments undertaken to characterize the nature of PP synthesized by the cultures identified a unique 66 kD protein. This protein was purified from chick tibial and calvarial bone and a polyclonal antibody was raised in rabbits. Ultrastructural immunocytochemistry using this antibody and the protein A-gold technique revealed specific immunolabelling over regions of mineralizing matrix in vitro, a reaction identical to that observed for the distribution of this 66 kD PP in vivo during embryonic tibial bone development in the chicken.

Animals↗