Search PubMed⌕ Search

Biomedical subjects

M Castagna

Publications and source records attributed to M Castagna.

At least 37 records · Page 2Linked to original sources
PubMed1990

[Role of protein kinase C in cell regulation and tumor promotion].

The signaling pathways which transfer information into the cell form a tissue-specific network. Protein kinase C (PKC) belongs to the inositol 1, 4, 5 trisphosphate/diacylglycerol (IP3/DG) pathway and plays a key role in cell regulation. The enzyme controls cell growth and functions through a set of negative and positive regulatory mechanisms. Some tumor promoters such as phorbol esters activate PKC by acting at the DG binding site. Others do not compete with DG and either activate PKC in the absence of phospholipids, such as arachidonic acid and bile salts, or require the presence of phospholipids, for instance a number of organic solvents. However, some promoters do not directly activate the enzyme although some of them appear to act elsewhere in the IP3/DG signaling pathway. The possibility that tumor promoters impair the expression of PKC is discussed.

Carcinogens↗
PubMed1989

Membrane-phorbol ester interactions monitored by circular dichroism.

The interaction of phorbol 12,13-dibutyrate (PDBu), 12-O-retinoylphorbol 13-acetate (RPA) and 12-O-tetradecanoylphorbol 13-acetate (TPA) with L-alpha-phosphatidylserine-containing small unilamellar vesicles or erythrocyte ghosts was monitored by circular dichroism (CD). No change in the CD spectra of PDBu was observed upon binding, while RPA and TPA spectra were slowly affected by the interaction. The changes in RPA and TPA spectra were assigned to the embedding of these molecules in the membrane bilayers. In the presence of 10(8) cells/ml, after one minute incubation, about 2 to 5% of the amount of phorbol ester added is embedded in the membrane. It is suggested that either phorbol esters entering the membrane is not a prerequisite for protein kinase C activation or the amount of phorbol esters necessary to activate protein kinase C is very small.

Circular Dichroism↗
PubMed1989

Calmodulin antagonist W-7 inhibits lysosomal sphingomyelinase activity in C6 glioma cells.

N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) is known to be a potent calmodulin antagonist and inhibitor of calmodulin-dependent protein kinases. W-7 and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7) are inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. In C6 glioma cells, W-7 and not H-7 inhibited dose-dependently acid sphingomyelinase, a result indicating the modulation of this lysosomal enzyme by a calmodulin-dependent system. Other lysosomal enzymes, such as beta-glucosidase, alpha-galactosidase, and arylsulfatase A, were unaffected by W-7 and H-7, a finding indicating a selective effect of W-7 on sphingomyelinase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Benzene-mediated protein kinase C activation.

Extracellular ligands transfer information into the cell through several pathways that operate in an integrated fashion. Protein kinase C, and enzyme that plays a pivotal role in signal transduction, is the molecular target for tumor promoters from the series of phorbol esters. A number of structurally unrelated tumor promoters also enhance protein kinase C, interacting or not interacting with the phorbol ester binding site. Evidence is provided that benzene potently activate protein kinase C in vitro, as well as in intact platelets. The drug does not compete for the phorbol ester binding site and probably affects the hydrophobic environment requires for full enzyme activation. Toluene is equally active. The relevance of the presented findings in the carcinogenic effects of benzene is discussed.

Animals↗
PubMed1989

Distribution of calcitonin- and somatostatin-containing cells in thyroid lymphoma and in Hashimoto's thyroiditis.

Eleven cases of thyroid lymphoma were studied by the immunoperoxidase avidin-biotin technique with calcitonin and somatostatin rabbit antisera. In 6 cases of non-Hodgkin lymphoma, in thyroid tissue residual to the lymphomatous infiltration, the C cell density was markedly increased and clustering was often observed; the C cells often took part in the follicular lining, frequently with polar distribution; these elements displayed a strong positivity for calcitonin, while the number of somatostatin-containing cells was lower and the staining less intense. In the only case of Hodgkin's lymphoma of the thyroid gland the staining was negative; in other 4 cases of non-Hodgkin lymphoma no residual thyroid tissue was found and the staining was also negative. As Hashimoto's thyroiditis is often associated with thyroid lymphoma, 13 cases of Hashimoto's thyroiditis were also studied; no C cells were observed and both stainings were negative. These data show that an increase in the C cell number may be a hallmark of thyroid lymphoma and that hyperplastic C cells show an intensive positivity for calcitonin. On the other hand, C cell hyperplasia is not present in Hashimoto's thyroiditis, in spite of the close association with thyroid lymphoma. Furthermore, we provide evidence that somatostatin-containing cells are present both in normal thyroid glands and in thyroid lymphoma.

Calcitonin↗
PubMed1989

[The role of calcium, diglyceride ester bindings and a synthetic polypeptide in protein kinase C activation].

Protein kinase C, which plays a significant role in the polyphosphoinositide pathway of transmembrane signaling, is activated by a large class of extracellular ligands including neurotransmitters, hormones and growth factors. Diacylglycerols are the intracellular mediators of protein kinase C activation. Tumor promoting phorbol esters mimic the diacylglycerol action in binding to the same site. Active diacylglycerols have the 1.2 sn configuration and saturated short chain or unsaturated long chain fatty acids. Alkyl analogs of diacylglycerols were devoid of activity when an ether bond was present in position 1, whereas activity of the alkyl analog in position 2 was retained. Protein kinase C activation and 3H-TPA binding to the enzyme occurred in the presence of 0.5 mM EGTA. Moreover it has been shown in vivo that full activation of the enzyme was obtained in the intact platelets loaded with an excess of Quin 2, prior to stimulation by phorbol esters. A peptide (residues 499-513) was synthesized which enhanced the affinity of protein kinase C for histone. It is suggested that it may be the receptor site for another peptide of the enzyme (residues 19 to 36) which behaves as a pseudosubstrate.

Animals↗
PubMed1988

Morphologic and antigenic properties of mouse mammary tumor virus produced in a hormone-responsive fashion by C57Bl/10 mammary tumors of non-viral origin.

Bl-MaTU/A1 mouse mammary tumor cells, derived from a C57B1/10 mammary adenocarcinoma induced by dimethylbenzanthracene and mammotropic hormones, express virus particles and proteins related to mouse mammary tumor virus (MMTV). Immunocytochemical analysis by means of monospecific and monoclonal anti-gp52 sera revealed a different localization of the main structural proteins of MMTV in Bl-MaTU/A1 and GR cells (the latter used as a positive virus-producing control). Immunoelectron microscopy of B-type particles budding from the microvilli of dexamethasone-stimulated Bl-MaTU/A1 cells showed remarkably weak reactivity of the viral envelope with anti-gp52-protein A-gold complexes as compared with that of dexamethasone-stimulated GR cells. Since Bl-MaTU/A1-associated MMTV originates from the amplified unit II of endogenous MMTV, which is altered probably within the env gene, the observed antigenic difference in the Bl-MaTU/A1-associated MMTV may be due to altered synthesis of gp52 glycoprotein in these cells.

Adenocarcinoma↗
PubMed1987

Alkyl analogs of diacylglycerol as activators of protein kinase C.

Diacylglycerols which activate protein kinase C have the 1,2-sn configuration. Short-chain saturated fatty acids or long-chain unsaturated fatty acids are required for supporting the potency of these lipids. Using alkyl analogs such as 1-O-decyl-2-O-decanoylglycerol, 1-O-decanoyl-2-O-decylglycerol, 1,2-O-didecylglycerol, 1-O-hexadecyl-2-O-acetylglycerol and 1-O-decyl-2-O-acetylglycerol, we showed that the ether bond was consistently associated with a loss of activity to varying extents. The results suggest that the ester bond in the 1-position is a major determinant of diacylglycerol-mediated protein kinase activation.

Animals↗
PubMed1987

Tumor promoter chloroform is a potent protein kinase C activator.

The major interaction site for tumor-promoting phorbol esters is the calcium-activated, phospholipid-dependent protein kinase (protein kinase C), a key-element in signal transduction. Binding of phorbol esters results in enzyme activation which mediates, at least in part, the action of these agents. We have investigated the effects of tumor promoter chloroform on protein kinase C activity. Like thrombin and 12-O-tetradecanoylphorbol-13-acetate (TPA), chloroform was able to activate protein kinase C in intact rabbit platelets. In addition, chloroform stimulated enzyme activity as well as TPA binding capacity in cell-free system. Scatchard analysis of the data has shown that chloroform increased the number of phorbol ester binding sites. Structurally related compounds, carbon tetrachloride and methylene chloride, activated the enzyme similarly.

Animals↗
PubMed1987

Mammary cancer antigen recognized by monoclonal antibody B72.3 in apocrine metaplasia of the human breast.

Monoclonal antibody B72.3 recognizing a pan-associated carcinoma antigen expressed also in metastatic human breast cancer cells has been tested using the avidin-biotin peroxidase method applied to paraffin-embedded sections in 50 samples of mammary tissue showing apocrine metaplasia and in 58 cases of other mild or severe focal epithelial proliferative changes of the breast, including mostly in situ lobular or ductal carcinomas collateral to clinical cancer removed after radical mastectomy. The antigen detected by this antibody was present in the apocrine cells of 48 cases (96%). In the majority of these cases the reactivity was localized on the luminal border of the apocrine cells and in the luminal secretion. But ten cases showed positive staining also in the cell cytoplasm either focal or diffuse. The normal structures and mild focal hyperplastic changes collateral to clinical cancer were, in the majority of the cases (43 of 55), negative, and, when positive, displayed positivity only at the luminal border. By contrast, the independent foci of in situ carcinoma (17 of 31 examined), the intraduct papillomas (seven cases of 14), and the intraductal component of breast carcinoma (seven cases of 17) were positive, displaying a cytoplasmic focal or diffuse staining. In conclusion, mammary apocrine metaplasia, a metaplastic change of the normal epithelium that has been associated with increased breast cancer risk, shares antigens in common with breast cancer cells and/or with cells showing severe atypia. The possible clinical significance of the site of antigenic expression (cytoplasm or luminal border) needs further investigation.

Antibodies, Monoclonal↗
PubMed1987

Benzene and toluene activate protein kinase C.

Protein kinase C plays a pivotal role in the transduction of signals controlling cell activation. A number of tumor promoters including phorbol esters activate the enzyme by substituting for diacylglycerol, the intracellular messenger of physiological ligands. In contrast, chloroform-induced protein kinase C activation does not appear to be mediated through the same mechanism. In vitro studies and experiments on intact platelets have revealed that benzene and toluene are also activators of protein kinase C. The data suggest that these drugs, which do not inhibit [3H]12-O-tetradecanoylphorbol-13-acetate binding to the enzyme, probably act in a chloroform-like manner.

Animals↗
PubMed1987

Phorbol esters as signal transducers and tumor promoters.

Extracellular ligands transfer information into the cell through various signaling pathways which operate in an integrated way. Oncogene proteins and tumor promoters cooperate to constitutively turn on the signaling pathways and lead to irreversible cell activation. The evidence that supports this concept is reviewed, with emphasis on the role of phorbol esters and protein kinase C in signal transduction and oncogenesis.

Animals↗
PubMed1985

Structural analogies between protein kinase C activators.

Phorbol esters and diacylglycerols activate protein kinase C but specific structural parameters appear to be required for the enzyme activation. We have analyzed the conformation of potent and not potent diacylglycerols and phorbol esters. The orientation of the CH20H group at C3 of 1,2 diolein is remarkably similar to that of the same group at C-20 of 4 beta phorbol didecanoate and crucial for potency in activating the enzyme. Our data suggest that the new conformational approach here described could be used to rationally design specific inhibitors preventing the effects of tumor promoters and to predict the structure of potential tumor promoters.

Acetylation↗
PubMed1985

Cholinergic and non-cholinergic forebrain projections to the interpeduncular nucleus.

A combined fluorescent retrograde tracing and acetylcholinesterase (AChE) histochemical technique was used for the study of some forebrain projections to the interpeduncular nucleus (IPN). After injections of a fluorescent tracer into the IPN, the distribution of AChE-containing and of fluorescent retrogradely labeled neurons was simultaneously studied in the habenular nuclei, medial septum and diagonal band of Broca. In all these regions, the majority of retrogradely labeled neurons also contained AChE: neurons located in the habenular nuclei stained lightly or moderately for the enzyme, while neurons located in the diagonal band and medial septum displayed intense AChE staining and were classified as putatively cholinergic perikarya. In all regions, a minority of labeled neurons did not stain for AChE, and were identified as non-cholinergic neurons projecting to the IPN. The present study shows the existence of a biochemical heterogeneity in the habenulo-interpeduncular and telencephalo-interpeduncular pathways, and indicates that the latter contains putatively cholinergic as well as non-cholinergic fibers.

Acetylcholinesterase↗