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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↗

PubMed2001

Protein kinase C alpha -mediated negative feedback regulation is responsible for the termination of insulin-like growth factor I-induced activation of nuclear phospholipase C beta1 in Swiss 3T3 cells.

Previous studies from several independent laboratories have demonstrated the existence of an autonomous phosphoinositide (PI) cycle within the nucleus, where it is involved in both cell proliferation and differentiation. Stimulation of Swiss 3T3 cells with insulin-like growth factor-I (IGF-I) has been shown to induce a transient and rapid increase in the activity of nuclear-localized phospholipase C (PLC) beta1, which in turn leads to the production of inositol trisphosphate and diacylglycerol in the nucleus. Nuclear diacylglycerol provides the driving force for the nuclear translocation of protein kinase C (PKC) alpha. Here, we report that treatment of Swiss 3T3 cells with Go6976, a selective inhibitor of PKC alpha, caused a sustained elevation of IGF-I-stimulated nuclear PLC activity. A time course study revealed an inverse relationship between nuclear PKC activity and the activity of nuclear PLC in IGF-I-treated cells. A time-dependent association between PKC alpha and PLC beta1 in the nucleus was also observed following IGF-I treatment. Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation. These results indicate that a negative feedback regulation of PLC beta1 by PKC alpha plays a critical role in the termination of the IGF-I-dependent signal that activates the nuclear PI cycle.

3T3 Cells↗

PubMed1997

Modulation of the apoptotic response of human myeloid leukemia cells to a diphtheria toxin granulocyte-macrophage colony-stimulating factor fusion protein.

It has previously been shown that human granulocyte-macrophage colony-stimulating factor (GM-CSF) can be fused to a truncated diphtheria toxin (DT) to produce a recombinant fusion toxin that kills GM-CSF receptor-bearing cells. We now report that DT388-GM-CSF induces apoptosis and inhibition of colony formation in semisolid medium in receptor positive cells, and that the induction of apoptosis correlates with GM-CSF-receptor occupancy at low ligand concentrations. Also, the induction of apoptosis correlates with the inhibition of protein synthesis and is inversely related to the amount of intracellular antiapoptotic proteins (Bcl2 and Bc1XL). Nine myeloid leukemia cells lines and four nonmyeloid leukemia cell lines were incubated with 0.7 nmol/L of 125I-GM-CSF in the presence or absence of excess cold GM-CSF and bound label measured. High affinity receptor numbers varied from 0 to 291 molecules per cell. Cells were incubated with varying concentrations of recombinant fusion toxin for 48 hours and incorporation of 3H-leucine (protein synthesis), segmentation of nuclei after DAPI staining (apoptosis), and colony formation in 0.2% agarose (clonogenicity) were measured. DT388-GM-CSF at 4 x 10(-9) mol/L inhibited colony formation 1.5 to 3.0 logs for receptor positive cell lines. Protein synthesis and apoptosis IC50s varied among cell lines from greater than 4 x 10(-9) mol/L to 3 x 10(-13) mol/L. GM-CSF-receptor occupancy at 0.7 nmol/L GM-CSF-ligand concentration correlated with the protein synthesis IC50. Similarly, the protein synthesis inhibition and apoptosis induction correlated well, except in cells overexpressing Bcl2 and BclXL, in which 25- to 150-fold inhibition of apoptosis was observed. We conclude that DT388-GM-CSF can kill acute myeloid leukemia blasts but that apoptotic sensitivities will depend on the presence of at least 100 high affinity GM-CSF receptors/cell and the absence of overexpressed antiapoptotic proteins.

Apoptosis↗

PubMed2003

Irreversible aggregation of recombinant bovine granulocyte-colony stimulating factor (bG-CSF) and implications for predicting protein shelf life.

The kinetics of irreversible aggregation of bovine Granulocyte-Colony Stimulating Factor (bG-CSF) in solution were investigated as a function of temperature (T), concentration, and pH, and analyzed in terms of an Extended Lumry-Eyring model of protein aggregation proceeding via a non-native conformational state. In the spirit of classic Lumry-Eyring models, the observed kinetics are separated into contributions from thermodynamic or conformational stability of unaggregated native and non-native states, and the intrinsic aggregation kinetics of non-native molecules. It is found that a detailed treatment of the intrinsic kinetics coupled with a two-state approximation of the reversible unfolding transition is sufficient to allow quantitative prediction of low-T stability from high-T data despite highly non-Arrhenius kinetics. Accounting for shifts in conformational equilibrium quantitatively captures the non-Arrhenius T dependence, without requiring the assumption of a change in the rate-determining step with T. From a more general perspective, the observed aggregation behavior of bG-CSF is consistent with the rate-determining step being aggregation at T below a crossover temperature T(x) that is inversely related to initial protein concentration. Above T(x), irreversible unfolding is presumably the rate-determining step. The results illustrate that protein aggregation kinetics can, in principle, be predicted quantitatively from so-called accelerated data provided the thermodynamic and kinetic components can be separately extrapolated to longer term storage conditions.

Algorithms↗

PubMed1995

Factors related to sex hormone binding globulin concentrations in women with anorexia nervosa.

The published reports concerning serum levels of sex hormone binding globulin (SHBG) in women with anorexia nervosa are few in number and controversial. Indeed, very little is known of the factors influencing SHBG concentrations in these patients. In an attempt to clarify this problem we evaluated serum levels of SHBG, estradiol, testosterone, luteinizing hormone, follicle stimulating hormone, triiodothyronine, thyroxine, their free fractions and insulin in 19 women with anorexia nervosa. Plasma glucose levels, total protein, triglycerides and cholesterol were also studied. Seven healthy women with normal weight and regular menstrual cycles served as controls. The serum concentrations of SHBG in patients with anorexia nervosa (165.27 +/- 63.5 nmol/l) were significantly higher (p < 0.01) than those in the control group (96.21 +/- 38.04 nmol/l), but the levels of estradiol, testosterone, free triiodothyronine and the ratio of testosterone to SHBG were significantly lower. An inverse correlation between SHBG and body weight (r = -0.761) was found in the patients. The alterations in SHBG concentrations were not associated with the changes in testosterone, gonadotropins, thyroid hormones and biochemical parameters. These findings suggest that body weight is one of the more important factors influencing the SHBG concentrations in women with anorexia nervosa.

Adolescent↗

PubMed2002

Proinflammatory cytokines but not acute phase serum amyloid A or C-reactive protein, downregulate paraoxonase 1 (PON1) expression by HepG2 cells.

The expression of paraoxonase1 (PON1) during inflammation has been investigated in vitro. The alteration of steady state PON1 mRNA in HepG2 cells by interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), was investigated relative to acute-phase serum amyloid A (A-SAA) mRNA. PON1 mRNA expression by HepG2 cells was decreased within three hours of stimulation by IL-1beta or TNF-alpha. Relative to PON1 mRNA expression, the pattern of steady state A-SAA mRNA expression was altered reciprocally and inversely by IL-1beta. These findings suggested that the decrease in serum PON activity after abdominal surgery in our previous clinical study may be ascribed to a decrease in steady state PON1 mRNA expression by liver with proinflammatory cytokines.

Apolipoproteins↗

PubMed1999

Nitric oxide regulation of asthmatic airway inflammation with segmental allergen challenge.

BACKGROUND: Despite evidence of increased nitric oxide (NO) in asthmatic compared with healthy individuals, the role of NO in airway inflammation is unclear. OBJECTIVE: The purpose of the study was to determine the in vivo effects of localized allergen challenge on airway NO levels and transcription factor activation. METHODS: In this study localized allergen challenge was used as a model of asthmatic exacerbation to determine the relationship of NO to airway inflammation. RESULTS: With allergen challenge, asthmatic patients had a rise in airway NO levels, whereas NO levels in healthy controls did not change. The increased NO in asthma with allergen challenge compared with healthy control subjects was associated with an increase in inflammatory cytokines (GM-CSF and macrophage inflammatory protein-1) in epithelial lining fluid and eosinophilic infiltrate in bronchoalveolar lavage fluid (BAL) and biopsy specimens. To investigate the mechanisms of cytokine gene expression, activation of the transcription factors activator protein-1 and nuclear factor-kappaB (NF-kappaB) in cells from BAL were evaluated. Activator protein-1 was not activated before or after local allergen challenge. In contrast, NF-kappaB activation was less in BAL cells from asthmatic patients with increased NO in comparison with controls. CONCLUSION: Our studies are the first to suggest an inverse correlation between NF-kappaB and airway NO in a localized segmental allergen challenge model in allergic asthmatic patients. The current study demonstrates that activation of the inflammatory response (eg, cytokines, cellular infiltrate) in allergic asthmatic patients is temporally associated with increased airway NO. We propose that NO that is up-regulated by cytokines is part of an autoregulatory feedback loop (ie, allergen challenge stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production).

Adult↗

PubMed2001

Transfer protein TraY of plasmid R1 stimulates TraI-catalyzed oriT cleavage in vivo.

The effect of TraY protein on TraI-catalyzed strand scission at the R1 transfer origin (oriT) in vivo was investigated. As expected, the cleavage reaction was not detected in Escherichia coli cells expressing tral and the integration host factor (IHF) in the absence of other transfer proteins. The TraM dependence of strand scission was found to be inversely correlated with the presence of TraY. Thus, the TraY and TraM proteins could each enhance cleaving activity at oriT in the absence of the other. In contrast, no detectable intracellular cleaving activity was exhibited by TraI in an IHF mutant strain despite the additional presence of both TraM and TraY. An essential role for IHF in this reaction in vivo is, therefore, implied. Mobilization experiments employing recombinant R1 oriT constructions and a heterologous conjugative helper plasmid were used to investigate the independent contributions of TraY and TraM to the R1 relaxosome during bacterial conjugation. In accordance with earlier observations, traY was dispensable for mobilization in the presence of traM, but mobilization did not occur in the absence of both traM and traY. Interestingly, although the cleavage assays demonstrate that TraM and TraY independently promote strand scission in vivo, TraM remained essential for mobilization of the R1 origin even in the presence of TraY. These findings suggest that, whereas TraY and TraM function may overlap to a certain extent in the R1 relaxosome, TraM additionally performs a second function that is essential for successful conjugative transmission of plasmid DNA.

Bacterial Proteins↗

PubMed2000

Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts.

BACKGROUND: Angiotensin II (Ang II) is implicated in cardiac remodeling and is increasingly recognized for its profibrotic activity. METHODS AND RESULTS: Because little is known about the direct cellular effects of Ang II on human cardiac fibroblasts, we isolated fibroblasts from ventricles of explanted human hearts and added Ang II (100 nmol/L) to determine its role in growth, extracellular matrix accumulation, and adhesion. To assess which Ang II receptor is involved, Ang II was added in the presence of irbesartan (10 micromol/L), a specific AT(1) receptor antagonist; PD 123319 (10 micromol/L), a specific AT(2) receptor antagonist, or divalinil (100 nmol/L), an AT(4) receptor inhibitor. In human ventricles (n=13), message levels of atrial natriuretic peptide and AT(1) receptor were inversely correlated, which suggests a decrease in AT(1) receptor expression with progressive heart failure. Northern analysis and fluorescence-activated cell sorting demonstrated AT(1) receptor in cultured human cardiac fibroblasts. Ang II increased mitogen-activated protein kinase activity and in DNA synthesis (5-fold, P<0.01) stimulated a 2-fold increase in transforming growth factor-beta(1) (P<0.05) mRNA levels at 2 hours and a 2-fold increase in laminin (P<0.05) and fibronectin (P<0.05) mRNA levels at 24 hours. Ang II also enhanced plasminogen activator inhibitor-1 expression, which inhibits metalloproteinases that degrade the extracellular matrix. All of these effects were inhibited by irbesartan but not PD 123319 or divalinil. In addition, Ang II increased cardiac fibroblast attachment to collagens I and III, which was associated with an increase in focal adhesion kinase activity. CONCLUSIONS: Activation of the AT(1) receptor in human heart promotes fibrosis. Ang II plays a novel role in stimulation of plasminogen activator inhibitor-1 expression and adhesion of cardiac fibroblasts to collagen.

Adolescent↗

PubMed2000

Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells.

Vascular endothelial growth factor (VEGF) induces adhesion molecules on endothelial cells during inflammation. Here we examined the mechanisms underlying VEGF-stimulated expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in human umbilical vein endothelial cells. VEGF (20 ng/ml) increased expression of ICAM-1, VCAM-1, and E-selectin mRNAs in a time-dependent manner. These effects were significantly suppressed by Flk-1/kinase-insert domain containing receptor (KDR) antagonist and by inhibitors of phospholipase C, nuclear factor (NF)-kappaB, sphingosine kinase, and protein kinase C, but they were not affected by inhibitors of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 or nitric-oxide synthase. Unexpectedly, the phosphatidylinositol (PI) 3'-kinase inhibitor wortmannin enhanced both basal and VEGF-stimulated adhesion molecule expression, whereas insulin, a PI 3'-kinase activator, suppressed both basal and VEGF-stimulated expression. Gel shift analysis revealed that VEGF stimulated NF-kappaB activity. This effect was inhibited by phospholipase C, NF-kappaB, or protein kinase C inhibitor. VEGF increased VCAM-1 and ICAM-1 protein levels and increased leukocyte adhesiveness in a NF-kappaB-dependent manner. These results suggest that VEGF-stimulated expression of ICAM-1, VCAM-1, and E-selectin mRNAs was mainly through NF-kappaB activation with PI 3'-kinase-mediated suppression, but was independent of nitric oxide and MEK. Thus, VEGF simultaneously activates two signal transduction pathways that have opposite functions in the induction of adhesion molecule expression. The existence of parallel inverse signaling implies that the induction of adhesion molecule expression by VEGF is very finely regulated.

Androstadienes↗

PubMed2002

Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis.

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in paracoccidioidomycosis were investigated in a prospective study. Patients were evaluated before treatment and 1 and 6 months after receiving antifungal therapy. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha plasma levels, C-reactive protein (CRP) concentrations, and erythrocyte sedimentation rate (ESR) were significantly higher in untreated patients than in control subjects. After 6 months of treatment, levels of the 3 cytokines, CRP concentrations, and the ESR decreased significantly. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) plasma levels were significantly lower in patients than in sex- and age-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6 plasma levels. This finding may be of pathogenetic significance in this disease and in other inflammatory states.

Adrenocorticotropic Hormone↗

PubMed1988

The use of molecular probes in the study of the action of histamine on macrophages.

The effect of histamine on the expression in vitro of C2, factor B and C3 genes in murine resident peritoneal macrophages was investigated. By measuring the levels of specific mRNA and the amount of the biosynthetically labelled gene products, we found that histamine decreases the biosynthesis of C2 and factor B. However, histamine had virtually no effect on the biosynthesis of C3 in the same cells. To clarify the mechanism of these effects, the H1 agonists (2-pyridylethylamine (PEA)and 2-methylhistamine), the H2-agonists (impromidine and 4-methyl-histamine), the H1-antagonist (chlorpheniramine) as well as the H2-antagonist (cimetidine) were also tested. We found that the inhibitory effect of histamine on C2 and factor B is produced only through H2 receptors. With the combination of histamine agonists and antagonists an inverse effect via H1- or H2-receptors was determined on the biosynthesis of C3. H1-receptor stimuli enhanced, and the stimulation of H2-receptors inhibited, C3 biosynthesis. All effects were pretranslational since the same results were obtained on mRNA and protein levels.

Animals↗

PubMedDate not supplied

Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease.

BACKGROUND: Recently it has been reported that activation of the inflammatory response system (IRS) may play a role in the aging process and in the pathogenesis of the degenerative changes associated with Alzheimer's disease (SDAT). The aims of the present study were to examine the peripheral IRS in normal aging and in SDAT patients. METHODS: Serum zinc (Zn), total serum protein (TSP), albumin (Alb), SP electrophoresis, and serum interleukin-6 (IL-6) and the stimulated production of tumor necrosis factor-alpha (TNFalpha) were determined in younger versus elderly healthy subjects and in SDAT patients vs. age-matched, healthy volunteers. RESULTS: Serum Zn and Alb were significantly lower in elderly than in younger healthy volunteers and were significantly and inversely correlated with age. The production of TNFalpha was significantly higher in elderly than in younger healthy volunteers and was significantly and positively correlated with age. In SDAT patients, no significant changes in serum Zn or TNFalpha production could be found. Serum Alb was significantly lower and serum IL-6 and the alpha1 and alpha2 globulin fractions significantly higher in SDAT patients than in controls. CONCLUSIONS: Activation of the IRS appears to accompany the normal aging process, i.e. lower serum Zn and Alb and increased TNFalpha production, as well as SDAT, i.e. lower serum Alb and increased serum IL-6 and alpha1 and alpha2 globulin fractions. The findings suggest that not all indicators of IRS activation in SDAT are related to those of the normal ageing process.

Adult↗

PubMed1991

Sequence of the cDNA encoding ovine tumor necrosis factor-alpha: problems with cloning by inverse PCR.

We have cloned and sequenced the ovine tumor necrosis factor-alpha (TNF-alpha)-encoding cDNA, using gene amplification by polymerase chain reaction (PCR) technology, to aid studies of assorted diseases in this species. We used primers selected from published TnfA sequences of other species on a cDNA template prepared from lipopolysaccharide-stimulated ovine alveolar macrophages, to generate a product representing the central region of the molecule. We then used a novel method based on 'inverse PCR' to generate a product containing the 5' and 3' ends of the molecule. Here, we present the complete sequence of the ovine TNF-alpha cDNA and compare it with other published TNF sequences. The cloned cDNA has a leader sequence of 156 bp followed by a protein-coding sequence of 702 bp and a 3'-untranslated region of 800 bp. The protein product of the gene is a protein of Mr = 25,586, 79% homologous to human TNF-alpha. An mRNA produced by alveolar macrophages, which hybridises to the cloned gene, is induced greatly, with a peak induction time of approx. 135 min, in response to stimulation by lipopolysaccharide and to plating on plastic. We also discuss the resolution of some artefacts of the inverse PCR technique.

Amino Acid Sequence↗

PubMed2001

Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: possible role in AP-1-mediated proliferation of ER-negative endometrial cancer.

OBJECTIVE: Tamoxifen is the most widely used antiestrogen to treat all stages of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen acts as a partial estrogen in the uterus and is known to increase the risk of endometrial cancer by two- to threefold. Recent evidence indicates that there is a connection between tamoxifen resistance and activation of the activator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKCalpha), an upstream activator of the AP-1 pathway, in hormone-independent breast cancer and antiestrogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormone-independent breast cancer and determine whether specific PKC isozyme alterations correlated with known clinicopathological features of endometrial cancer. METHODS: The PKC isozyme profile of endometrial carcinomas from 42 patients who were not previously exposed to antiestrogens was examined by Western blot. The relationship between PKC isozyme expression and key prognostic factors for endometrial carcinoma including hormone receptor status, tumor grade, stage, size, and depth of myometrial invasion was examined using the Spearman's rho correlation coefficient. RESULTS: As previously found in breast cancers, PKCalpha and estrogen receptor alpha (ERalpha) expression are inversely related (r(s) = -0.35, P = 0.046). We report significant inverse correlations among ER/progesterone receptor (PR) expression and tumor grade (r(s) = -0.49, P = 0.001 and r(s) = -0.44, P = 0.004, respectively), ER, and depth of myometrial invasion (r(s) = -0.40, P = 0.009). There were no other significant correlations between PKC isozyme expression and other key prognostic factors examined. CONCLUSION: This study indicates that, similar to what was previously observed in breast cancer, PKCalpha and ER expression is inversely related in endometrial cancer. PKCalpha expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCalpha overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.

Cell Division↗

PubMed1992

Expression of human prostatic acid phosphatase activity and the growth of prostate carcinoma cells.

Human prostatic acid phosphatase (PAcP) is a tissue-specific differentiation antigen and is the major phosphotyrosyl (p-tyr) protein phosphatase in normal differentiated prostate epithelial cells. In prostate carcinomas, cellular PAcP has a low expression. We examined the expression of cellular PAcP activity and its correlation with cell growth that may lead us to understand the role of tyrosine phosphorylation in human prostate cells. LNCaP cells, which expressed the highest cellular PAcP activity, had the slowest growth rate and the lowest p-tyr level among three human prostate carcinoma cell lines: LNCaP, DU145, and PC-3. This inverse correlation was further examined in LNCaP cells, since these cells remain hormone-sensitive. Androgen, a classical stimulator of prostate cells, stimulated the growth of LNCaP cells while cellular PAcP activity decreased and p-tyr levels increased. This phenomenon was also observed when cells were treated with epidermal growth factor and fetal bovine serum. Both epidermal growth factor and fetal bovine serum stimulated the growth of LNCaP cells whereas cellular PAcP activity decreased. Furthermore, when cell growth was arrested at low temperatures (23 degrees C), cellular PAcP activity was elevated. To establish the relationship of cellular PAcP activity with cell growth rate, we transfected a complementary DNA encoding the full length PAcP protein into another human prostate carcinoma line, PC-3, that lacks endogenous PAcP. Two stable transfectants, designated PC-18 and PC-416 cells, were obtained and shown to express PAcP mRNA transcribed from the transfected complementary DNA. The expression of PAcP activity in PC-416 cells, but not PC-18 cells, was associated with a lower p-tyr level and a slower growth rate than control cells transfected with the expression vector alone. In conclusion, in LNCaP cells, the stimulated cell growth is associated with an increased p-tyr level and a decreased cellular PAcP activity. In PAcP complementary DNA-transfected PC-416 cells, the low level of p-tyr corresponds to a slow growth rate.

Acid Phosphatase↗

PubMed2000

Influence of decorin expression on transforming growth factor-beta-mediated collagen gel retraction and biglycan induction.

Complex formation of transforming growth factor-beta (TGF-beta) with the small proteoglycan decorin has been considered to inactivate the cytokine. However, neither the TGF-beta-mediated stimulation of the retraction of collagen lattices in culture nor the enhanced transcription of biglycan were influenced by an excess of native decorin in the culture medium. In contrast, when MG-63 osteosarcoma cells were transfected with sense- or antisense-decorin-cDNA, which led to an over- or under-expression of the proteoglycan, they responded to TGF-beta differently. An inverse correlation between decorin expression and the TGF-beta-mediated stimulation of collagen gel retraction and biglycan induction, respectively, was found. These results are best explained by assuming that decorin is not inactivating but sequestering TGF-beta in the extracellular matrix.

Biglycan↗

PubMedDate not supplied

Histochemically demonstrable protein tyrosine phosphatase in human breast and colorectal cancer: large decrease in its activity in colorectal cancer suggests a tumor suppressor role in colorectal mucosal cells.

Many oncogene products and growth factor receptors are protein tyrosine kinases, and exert their cellular effects by the phosphorylation of tyrosyl residues of effector proteins. The balance and dynamic renewal of phosphotyrosine proteins are also regulated by protein tyrosine phosphatases (PTPs), whose inhibition under experimental conditions causes cellular proliferation and transformation, with a concomitant increase in phosphotyrosine protein content. Inverse effects are obtained by increasing PTP activity. On the basis of these effects, PTPs might also function as tumor suppressors in human tissues. This possibility was further investigated here by demonstrating PTP and phosphotyrosine protein content with histochemical techniques. In normal human breast tissue PTP activity was low and in the majority of breast cancers the activity was increased and exhibited great variation between different cases. When the relationship of phosphotyrosine protein content with PTP was evaluated, no inverse dependence was detected, suggesting that in human breast tissue and cancer PTP may not show tumor suppressor activity. In normal colorectal mucosae PTP activity was high, while in all colorectal cancers it was very low, constituting only 14% of the activity present in normal mucosal cells. The great drop in PTP activity together with reported alterations in a gene encoding a PTP and in a chromosome containing a PTP gene in colorectal cancer strongly suggest that PTP may function as a tumor suppressor in human colorectal mucosae. The decrease in PTP activity may be one factor stimulating or causing neoplastic proliferation in multistep colorectal carcinogenesis.

Adenocarcinoma↗