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PubMed2004

EGF mediates multiple signals: dependence on the conditions.

Epidermal growth factor (EGF) has been reported to both increase and decrease proliferation and apoptosis. In KB cells, EGF-induced alteration in proliferation and apoptosis are concentration and time dependent. High concentrations of EGF (10(-7) and 10(-8) M) stimulated proliferation and inhibited apoptosis at 24 h, with apoptosis increasing with prolonged exposure. Low concentrations of EGF (10(-10)-10(-11) M) inhibited apoptosis without affecting proliferation. EGFR protein expression was downregulated at high and upregulated at low EGF concentrations. Significant inverse correlation was shown between EGFR expression level and apoptosis. These results suggest the EGF receptor involvement in the modulation of apoptosis and the role of EGF anti-apoptotic effects in EGF-induced apoptosis.

Apoptosis↗
PubMed1992

Transcriptional repression of the neu protooncogene by estrogen stimulated estrogen receptor.

Both neu gene overexpression and loss of estrogen receptor (ER) expression have been found to correlate with a poor prognosis in human breast cancer. Studies of breast tumor specimens have suggested that these two factors are not independent, leading us to hypothesize that there is a causal relationship between loss of ER and overexpression of neu. In this report, we confirm that ER can negatively regulate the expression of the neu gene protein product, p185neu, in two ER positive but not an ER negative breast cancer cell line(s). We have produced sublines which stably express human ER from a previously ER negative human breast cancer cell line. We demonstrate that the expression of ER in these cell lines is sufficient to confer the ability to respond to estradiol by down-regulating neu expression at both the protein and RNA levels. Utilizing neu promoter-chloramphenicol acetyltransferase constructs in transient cotransfection assays, we have also shown that this regulation occurs at the transcriptional level and requires the presence of both ER and estradiol. Furthermore, utilizing promoter deletion constructs, we provide evidence that a 140-base pair region of the neu promoter is required for this transcriptional regulation. When placed in a heterologous promoter, this 140-base pair region allows transcriptional repression by estradiol stimulated ER; thus, it represents an estrogen responsive region within the neu promoter. Finally, we have used gel mobility shift analysis to demonstrate an alteration in the nuclear factor(s) binding to this promoter region in estradiol stimulated versus estradiol deprived breast cancer cells. This study provides the first evidence that the inverse clinical correlation between neu and ER expression may be due to transcriptional repression of neu by estradiol stimulated ER.

Down-Regulation↗
PubMed1984

[Studies of the cellular immune response in patients with urinary bladder carcinoma. X. Evaluation of serum IAP and ASP levels].

Serum levels of immunosuppressive acidic protein (IAP) and acid soluble glycoprotein (ASP) were measured in 48 patients with urinary bladder carcinoma and 51 control subjects. Both IAP and ASP levels were significantly higher in the patients than in the control subjects, and the increase of these two serum substances seemed to be closely related to grading and staging of urinary bladder carcinoma. In many patients, serum IAP and ASP levels decreased after resection of tumors. There was an inverse correlation between IAP or ASP level and phytohemagglutinin (PHA)-induced lymphocyte blastogenesis (stimulation index, SI). This suggested an immunosuppressive effect of these serum factors. After chemotherapy of urinary bladder carcinoma, both IAP and ASP levels would decrease. It is suggested that serum IAP and ASP levels could be good indicators for evaluating the effect of chemotherapy.

Aged↗
PubMed2004

Plasminogen activator inhibitor-1 increases the expression of VEGF in human glioma cells.

The level of plasminogen activator inhibitor-1 (PAI-1) in tumor tissue has been shown to be an independent negative prognostic factor in different cancers. There are several proposed reasons for this, among these, the influence of PAI-1 on tumor neovascularization and cell migration. We report that PAI-1 stimulates expression and release of vascular endothelial growth factor (VEGF) in the human glioma cell line D54Mg, and thereby stimulates the proliferation of human umbilical vein endothelial cells (HUVEC) in vitro. To search for possible molecular effects of PAI-1 on malignant cells, cDNA array hybridization analysis of D54Mg glioma cells transfected with an adenoviral PAI-1 expression vector was performed. This revealed that the VEGF response was accompanied with the simultaneous upregulation of GADD153, Rho GTPase activating protein 4 (p115), Collagen type VI alpha 1 and cell division cycle 42 (CDC42) transcripts. Exogenous treatment of D54Mg cells with a constitutively active recombinant PAI-1 protein confirmed an upregulation of VEGF expression in a time- and dose-dependent manner, and supernatants from such cultures stimulated the proliferation of human umbilical vein endothelial cells in vitro. In 44 human glioma biopsies, patients, the protein levels of PAI-1 correlated strongly with the levels of VEGF in the tumor tissues. Whereas VEGF expression correlated inversely with survival, there was no statistically significant prediction of survival by PAI-1 in this group of patients. These clinical data support and strengthen the hypothesis that PAI-1 is one of the factors regulating and inducing the VEGF expression in human gliomas. The induction of VEGF expression and thus endothelial cell proliferation may represent an as yet undiscovered mechanism whereby PAI-1 contributes to tumor neoangiogenesis.

Adenoviridae↗
PubMed2006

M-CSF induces the stable interaction of cFms with alphaVbeta3 integrin in osteoclasts.

The macrophage colony stimulating factor receptor (cFms) and alpha(V)beta(3) integrin are both abundantly expressed and play critical roles in the differentiation, survival and migration of osteoclasts. We have previously demonstrated that cross-talk between cFms- and alpha(V)beta(3)-mediated signaling pathways regulated the cytoskeletal organization required for osteoclast migration. To investigate the nature of interaction between the two receptors, we sequentially used anion-exchange chromatography and immunoprecipitation to purify alpha(V)beta(3)-associated protein complexes. We have demonstrated that cFms stably associated with alpha(V)beta(3) in osteoclasts during adhesion, and that the association was induced by macrophage colony stimulating factor (M-CSF) stimulation. However, the kinetics of association of alpha(V)beta(3) and cFms did not correlate with the kinetics of tyrosine phosphorylation of cFms. Instead, maximally observed alpha(V)beta(3)/cFms association was after the peak of cFms tyrosine phosphorylation and correlated inversely with the total amount of cFms remaining. Furthermore, the complex containing cFms and alpha(V)beta(3) also contained a number of other signaling molecules including Pyk2, p130(Cas) and c-Cbl, known downstream regulators of the integrin-mediated signaling pathways in osteoclasts. In the presence of M-CSF, co-localization of alpha(V)beta(3) integrin and cFms was identified in the podosomal actin ring of the osteoclast during adhesion on glass. Interestingly, co-localization of both receptors was not found in the sealing zone, but in punctate structures associated with adhesion- or transcytosis-like structures in osteoclasts on bone. Taken together, we suggest that the association of alpha(V)beta(3) and cFms could be the result of signaling following tyrosine phosphorylation of cFms. The recruitment of cFms to alpha(V)beta(3) integrin may be an integral part of a larger signaling complex via which both of adhesion- and growth factor receptors coordinately regulate osteoclast adhesion, motility and membrane trafficking.

Animals↗
PubMed2004

Locally delivered rhBMP-2 enhances bone ingrowth and gap healing in a canine model.

The purpose of the present study was to determine if recombinant human bone morphogenetic protein-2 (rhBMP-2) enhances bone ingrowth into porous-coated implants and gap healing around the implants. In the presence of a 3-mm gap between the implant and host bone, porous-coated implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs. In three treatment groups, the test implant was treated with HA/TCP and rhBMP-2 in buffer at a dose of 100 microg/implant (n=5), 400 microg/implant (n=6), or 800 microg/implant (n=5) and placed in the left humerus. In these same animals, an internal control implant was treated only with HA/TCP and buffer and placed in the right humerus. These groups were compared with a previously reported external control group of seven animals in which no growth factor was delivered [J. Orthop. Res. 19 (2001) 85]. The BMP treated implants in the two lower dose groups had significantly more bone ingrowth than the external controls with the greatest effect in the 100 g/implant group (a 3.5-fold increase over the external control, p=0.008). All three dose groups had significantly more bone formation in the 3-mm gap surrounding the BMP treated implants than the external controls with the greatest effect in the 800 microg group (2.9-fold increase, p<0.001). Thus, application of rhBMP-2 to a porous-coated implant stimulated local bone ingrowth and gap healing. The enhancement of bone formation within the implant (bone ingrowth) was inversely related to dose.

Animals↗
PubMed2004

Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development.

Angiogenesis does not normally occur in most adult tissues. However, in the ovary, there are cyclical vascular changes including angiogenesis that involve the interaction of numerous cytokines and growth factors. Angiogenic processes are regulated by a balance between pro- and antiangiogenic factors. The purpose of this study was to determine the expression of the antiangiogenic thrombospondin family and proangiogenic vascular endothelial growth factor (VEGF) in various sizes of healthy bovine follicles. Ovaries were collected from slaughterhouse animals and healthy follicles were sorted based on size (< 0.5 cm, small; 0.5-1.0 cm, medium; >1.0 cm, large). Thrombospondin (TSP) protein levels were significantly higher in small follicles. Immunohistochemistry confirmed the granulosa layer as the primary area within the follicle involved in TSP generation and that small follicles had the highest proportion of immunopositive cells. TSP-1 and -2 mRNA levels were significantly higher in small follicles than either medium or large follicles. TSP colocalized with CD36 on granulosa cells (GC) in the follicle and in cultured cells. In contrast with TSP, VEGF expression increased during growth and development of the follicle. FSH stimulated GC expression of TSP, while LH had no effect. In summary, TSP-1 and -2 were coordinately expressed in the extravascular compartment of the ovary during early follicle development. VEGF was inversely expressed, with expression increasing as follicles developed. Regulated expression and localization of these proteins suggests that they may be involved in regulating growth and development of the follicle in a novel fashion.

Animals↗
PubMed2001

Expression of vascular endothelial growth factor receptors in smooth muscle cells.

Vascular Endothelial Growth Factor (VEGF) has been typically considered to be an endothelial-specific growth factor. However, it was recently demonstrated that VEGF can interact with non endothelial cells. In this study, we tested whether vascular smooth muscles cells (VSMCs) can express VEGF receptors, such as flk-1, flt-1, and neuropilin (NP)-1, and respond to VEGF in vitro. In cultured VSMCs, flk-1 and flt-1 expression was inversely related to cell density. The expression of flk-1 was down-regulated with increasing passage numbers. However, NP-1 levels were not affected by cell density or passage numbers. Flk-1, Flt-1, and NP-1 protein levels were confirmed by Western Blotting. Although the functional mature form of Flk-1 protein is expressed at low levels in VSMCs, phosphorylation of Flk-1 following VEGF(165) stimulation was still observed. SMCs migrated significantly in response to VEGF(165) and VEGF-E, whereas Placenta Growth Factor (PlGF) induced migration only at higher concentrations. Since VEGF-E is a specific activator of flk-1 while PlGF specifically activates only flt-1, SMC migration induced by VEGF(165) is likely to be mediated primarily through the flk-1 receptor. VSMCs did not significantly proliferate in response to VEGF(165), PlGF, and VEGF-E. In conclusion, our studies demonstrate the presence of VEGF receptors on VSMCs that are functional. These studies also indicate that in vivo, VEGF may play a role in modulating the response of VSMCs.

Animals↗
PubMed1999

Relationship between molecular mass and duration of activity of polyethylene glycol conjugated granulocyte colony-stimulating factor mutein.

Proteins conjugated with polyethylene glycol (PEG) have increased in vivo activity compared to native proteins. We examined the activity of a variety of PEG conjugates prepared with a recombinant mutein of granulocyte colony-stimulating factor (nartograstim [NTG], KW-2228). The total PEG mass was varied by the number and size of the PEG molecules conjugated. In vitro activity, determined using a proliferation assay with G-NFS-60 cells, demonstrated an inverse relationship between PEG mass and concentration required for half-maximal proliferation. In vivo activity was examined by injecting compounds subcutaneously into normal mice and determining neutrophil counts at various times. Initial experiments in C57BL/6J mice indicated that neutrophil levels were significantly elevated 5 days after a single injection of 25 micrograms/mouse of each PEG-NTG preparation. More detailed experiments were performed with several of the preparations in C3H/HeJ mice lacking endotoxin receptors. The results demonstrated that the time after injection at which neutrophil numbers reached a maximum increased with increasing size of PEG. Similar results were obtained with purified preparations containing 1, 2, or 3 units of 20-kDa PEG per molecule of NTG, showing that increasing the extent of PEGylation also increases in vivo activity. Dose-response studies with the 20-kDa PEG-NTG demonstrated a plateau at doses > 2.7 micrograms/mouse at day 3. The plateau dose increased to 8.4 micrograms/mouse at day 5, and no plateau was evident at the highest dose tested (50 micrograms/mL) at days 7 and 10. These results demonstrate that elevated neutrophil levels can be maintained for extended periods following single administration of high-molecular-weight PEG-NTG.

Animals↗
PubMed1987

Cell-density-dependent uptake of chylomicron remnants in rat hepatocyte monolayers. Effects of compactin and mevalonic acid.

In rat hepatocytes cultured in lipoprotein-deficient serum, the uptake and degradation of chylomicron remnant cholesteryl ester per mg cell protein varies inversely with cell density. Compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase, stimulates the uptake at all cell densities. Mevalonic acid, on the other hand, can suppress a significant part of the remnant uptake. Chylomicron remnant uptake in hepatocyte cultures can thus be influenced by factors known to regulate the apolipoprotein-BE receptor activity.

Animals↗
PubMed1996

Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival.

The relationships between the nervous and the immune systems raise the question of whether neurotrophic factors, in addition to the regulation of neural cell ontogeny, may influence lymphocyte development. We report in this work that the pattern of neurotrophin receptor expression depends on the developmental stage of T cells. The presence of nerve growth factor receptor trkA could not be detected in any of the thymocyte subsets, whereas brain-derived neurotrophic factor (BDNF) receptor trkB was expressed in all thymocyte subpopulations. Interestingly, both trkB mRNA and protein expression inversely correlated with the maturation stage and the differentiation potential of thymocytes, being more expressed in CD4-8- immature thymocytes and progressively declining in CD8+ and CD4+ single-positive and CD4+8+ more mature thymocytes. The developmentally regulated expression of trkB is further shown by the inhibition or enhancement of trkB expression induced by signals that either trigger or impair the transition from immature to more differentiated stages of the thymocyte developmental pathway. Signals generated following the interaction of BDNF with trkB receptor resulted in the stimulation of trkB autophosphorylation and in the up-regulation of the expression of the c-fos gene in CD4-8- cells and enhanced thymocyte survival. Finally, BDNF is expressed in thymic stroma and is further up-regulated by signals generated by the thymocyte/stromal cell interaction. These data suggest that BDNF may be a novel survival factor for thymocyte precursors and support the presence of developmentally regulated feedback mechanisms based on autocrine/paracrine neurotrophin/receptor interactions that may be involved in the thymocyte differentiation process.

Animals↗
PubMed1992

In vitro neurogenesis by neuronal precursor cells derived from the adult songbird brain.

The vocal control nucleus of the adult songbird forebrain, HVc, exhibits de novo neurogenesis in adulthood, with the production of new neurons from precursor cells located in the overlying ventricular zone (Goldman and Nottebohm, 1983). We previously established that explants derived from neurogenic regions of the adult canary forebrain could be maintained in vitro, under conditions that permitted the migration and differentiation of those new neurons previously generated in vivo (Goldman, 1990). However, we found no evidence for continued neuronal mitogenesis in these cultures, which were raised in high concentrations of serum. In the present study, we investigated the permissive conditions for in vitro neurogenesis by these adult forebrain-derived ventricular zone explants. When HVc explants derived from adult zebra finches were maintained in low-serum medium, in vitro neurogenesis could be demonstrated by 3H-thymidine uptake as long as 5 days after explantation. Immunocytochemistry for microtubule-associated protein-2 followed by autoradiography confirmed the neuronal identity of these 3H-thymidine-incorporating cells. In vitro neuronal production occurred in an inverse relation to the serum concentration: Over the range of 2.5-25% fetal bovine serum, neuronal 3H-thymidine labeling was most frequent in those cultures exposed to the lowest serum levels. This facilitation of in vitro neuronal mitogenesis by serum depletion suggests that fetal serum may contain factors that inhibit the division of adult-derived neuronal precursor cells, either directly or by agents released by serum-stimulated glial or ependymal cells.

Animals↗
PubMed1986

Partial separation and functional characterization of guinea pig basophil-stimulating factor.

We have previously described T lymphocyte dependent guinea pig basophil growth from bone marrow precursors in vitro. In the current studies, basophil-stimulating factor (BSF) present in mitogen-stimulated splenic conditioned medium (CM) has been functionally characterized, utilizing an assay for BSF on nonadherent bone marrow target cells. BSF was found to be heat stable, nondialyzable, and inactivated by proteases. Monosaccharides known to inhibit guinea pig lymphokines yielded a unique profile of inhibition of BSF activity and nonidentity of BSF with guinea pig migration inhibition factor, interleukins 1 or 2, and granulocyte-macrophage colony-stimulating activity, from which BSF could be separated after gel filtration. BSF-containing CM also had no detectable interleukin-3 activity as measured in a murine assay. An inverse relation was found between interleukin 2 and BSF production by peritoneal exudate T cells (PEL) stimulated with antigen. Fractionation of serum-containing and serum-free CM demonstrated a molecular size for BSF of 50,000-65,000 daltons. Guinea pig BSF is a distinct T cell dependent lymphokine with an active protein moiety which may interact with target bone marrow cells through a cell surface carbohydrate receptor.

Animals↗
PubMed2005

Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia.

Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients. We report here that although no such mutations were detected in 44 adult leukemia patients screened, Shp2 expression levels were significantly elevated in primary leukemia cells and leukemia cell lines, as compared with normal hematopoietic progenitor cells. The Shp2 protein amounts correlated well with the hyperproliferative capacity but were inversely associated with the differentiation degree of leukemia cells. Suppression of Shp2 expression induced apoptosis and inhibition of leukemic cell clonogenic growth. Notably, the majority of Shp2 was preferentially localized to the plasma membrane and was constitutively phosphorylated on tyrosine in leukemia cells, and also in normal hematopoietic cells following mitogenic stimulation. Based on these results, we propose that aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis.

Adolescent↗
PubMed2001

eIF4G functionally differs from eIFiso4G in promoting internal initiation, cap-independent translation, and translation of structured mRNAs.

Eukaryotic initiation factor (eIF) 4G plays an important role in assembling the initiation complex required for ribosome binding to an mRNA. Plants, animals, and yeast each express two eIF4G homologs, which share only 30, 46, and 53% identity, respectively. We have examined the functional differences between plant eIF4G proteins, referred to as eIF4G and eIFiso4G, when present as subunits of eIF4F and eIFiso4F, respectively. The degree to which a 5'-cap stimulated translation was inversely correlated with the concentration of eIF4F or eIFiso4F and required the poly(A)-binding protein for optimal function. Although eIF4F and eIFiso4F directed translation of unstructured mRNAs, eIF4F supported translation of an mRNA containing 5'-proximal secondary structure substantially better than did eIFiso4F. Moreover, eIF4F stimulated translation from uncapped monocistronic or dicistronic mRNAs to a greater extent than did eIFiso4F. These data suggest that at least some functions of plant eIFiso4F and eIF4F have diverged in that eIFiso4F promotes translation preferentially from unstructured mRNAs, whereas eIF4F can promote translation also from mRNAs that contain a structured 5'-leader and that are uncapped or contain multiple cistrons. This ability may also enable eIF4F to promote translation from standard mRNAs under cellular conditions in which cap-dependent translation is inhibited.

5' Untranslated Regions↗
PubMed1989

Regulation of growth hormone-independent insulin-like growth factor-binding protein (BP-28) in cultured human fetal liver explants.

Cultured human fetal liver explants were used to study regulation of the GH-independent insulin-like growth factor-binding protein (BP-28). BP-28 was produced by fetal liver explants at approximately 200 ng/mg total tissue protein.day between days 3 and 6 in culture and was inhibited 60% after 3-day exposure to cycloheximide (10 micrograms/mL). BP-28 production was stimulated over 3-fold by 20 mmol/L theophylline, over 2-fold by 30 mumol/L forskolin, and 90% by 10 micrograms/mL glucagon. The glucose concentration in the medium inversely regulated BP-28 production, which was 68% higher in 2 mmol/L glucose than in 30 mmol/L glucose (P less than 0.001); in contrast, albumin production was 40% lower in 2 mmol/L glucose than in 30 mmol/L (P less than 0.05). BP-28 levels were inhibited 50% by 300 nmol/L insulin or 3 mumol/L dexamethasone. In acid extracts of cultured tissue, BP-28 levels were less than 10% of the amount secreted in 48 h. These results are consistent with the conclusion that intracellular glucose availability is an important regulator of hepatic BP-28 synthesis.

Amniotic Fluid↗
PubMed2006

Pituitary-gonadal hormones and interleukin patterns in leprosy.

The functional status of pituitary-gonadal hormones and their relationship to the pattern of inflammatory cytokines in the lepromatous (LL/BL) and tuberculoid (TT/BT) poles of leprosy were investigated. Gonadotropins [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha and C-reactive protein (CRP) concentrations and erythrocyte sedimentation rate (ESR) were significantly higher in LL/BL leprosy patients than in controls and were not different from controls in TT/BT patients. LH and FSH were positively correlated with IL-1beta, IL-6 and TNF-alpha, and CRP concentrations and ESR. Testosterone plasma levels were significantly decreased in LL/BL patients and not different in TT/BT patients compared with controls. In addition, testosterone levels were inversely correlated with IL-6 and TNF-alpha. Prolactin plasma levels of both LL/BL and TT/BT patients were not different when compared with those of controls. There was a significant positive correlation between IL-6 and TNF-alpha plasma levels and ESR and CRP concentrations. IL-1beta was positively correlated with ESR but not with CRP. The significant correlations between gonadotropins and testosterone and cytokines in leprosy patients suggest that cytokines may have a direct influence at testicular level and may be of pathogenetic significance in leprosy and in other inflammatory states involving reproductive dysfunction.

Adult↗
PubMed1985

Urea synthesis in the canine kidney.

The ability of the kidney to synthesize urea is of interest and some controversy. We tested the hypothesis that low plasma urea concentrations would stimulate renal urea synthesis, thereby enhancing urinary concentrating ability. We defined a ratio of specific activity of plasma/specific activity of urine (SA ratio) greater than 1.0 as indicative of de novo intrarenal urea synthesis. We studied dogs on 3 dietary regimens: (1) commercial chow ad libitum; (2) restricted rations of the same chow; (3) protein-free diet ad libitum with vitamin/mineral supplement. A significant inverse relationship between plasma urea concentration and SA ratio was seen only in the ration-restricted group, despite the fact that plasma urea concentrations in this group were highest of the three groups. In addition, dogs in this group were more likely to demonstrate renal urea synthesis than dogs in the other groups. Thus, the dog kidney is capable of de novo urea synthesis, but a reduced plasma urea concentration does not necessarily stimulate this metabolic activity. Other factors in addition to the plasma urea concentration appear to be involved in the regulation of renal urea synthesis.

Animals↗