Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A single intubation of 7,12-dimethylbenz(a)anthracene (DMBA) (20 mg in 1 ml sesame oil) to female Sprague-Dawley rats at 50 days of age produces primary mammary carcinomas in 80% of rats at 100 to 150 days of age. Administration of N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate (DBcAMP) p.o. beginning at 1 day prior to DMBA intubation resulted in marked delay and reduction of tumor production: only 15% as many DBcAMP-treated rats had tumors as in the control group (DMBA only) with 60 days of delay in the first tumor appearance. DMBA-induced tumor production was preceded by changes in the cyclic adenosine 3':5'-monophosphate (cAMP) metabolism and protein kinase of the mammary gland. Within 24 hr post-DMBA intubation, the intracellular cAMP level and adenylate cyclase activity increased with an increase in type I isozyme of cAMP-dependent protein kinase, a form which has been associated with increased proliferative activity and a less differentiated cellular state in other tissues. The increases in cAMP level, adenylate cyclase activity, and the protein kinase activity were transient, and the values decreased to below the control values by Day 10 post-DMBA intubation. In mammary glands of rats that had received DBcAMP, the cAMP level and protein kinase isozyme pattern were similar to those of older rats that are no longer susceptible to the carcinogen. The inhibitory effect on DMBA-induced carcinogenesis may be related to the modifications that DBcAMP induces on cAMP level, adenylate cyclase activity, and cAMP-dependent protein kinase of the mammary gland.
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PMID:Anticarcinogenic effect of N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate on 7,12-dimethylbenz(a)anthracene mammary tumor induction in the rat and its relationship to cyclic adenosine 3':5'-monophosphate metabolism and protein kinase. 630 67

The ability of the phorbol ester tumor promoter 12-O-tetradecanoylphorbol- 13-acetate (TPA) to lead to the activation of cyclic adenosine 3':5'-monophosphate (cAMP)-dependent protein kinase was investigated in three cell lines. In the Reuber H35 hepatoma cells, TPA (1.6 microM) led to an increase in the protein kinase activity ratio from a value of 0.13 in control cultures to 0.40 in the stimulated cells within 30 min of addition. A specific fluorescent cytochemical procedure was further utilized to study the intracellular localization of the free catalytic subunit following activation of the holoenzyme by TPA. A marked increase in cytoplasmic and nucleolar fluorescence indicative of the appearance of the free catalytic subunit (activation of cAMP-dependent protein kinase) in these cellular compartments was observed in both Reuber H35 hepatoma and Chinese hamster ovary 10001 cells incubated with TPA (1.6 microM) for 30 min. In the H35 cells monitored with the cytochemical probe for the catalytic subunit, protein kinase was activated within 5 min of the addition of TPA (1.6 microM) with 0.16 microM TPA in the culture medium resulting in the maximal degree of activation. No increase in intracellular fluorescence throughout a 40-min period was observed in a cAMP-dependent protein kinase-deficient mutant strain Chinese hamster ovary 10260 cells incubated with TPA. These studies indicate that, while TPA does lead to the marked activation of cAMP-dependent protein kinase in at least two cell types shown to be responsive to TPA, this activation may be only one of several rapid events which mediate the many specific effects of the phorbol esters.
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PMID:Activation of cyclic adenosine 3':5'-monophosphate-dependent protein kinase in H35 hepatoma and Chinese hamster ovary cells by a phorbol ester tumor promoter. 630 80

An important portion of the protein kinase activity in the 7,12-dimethylbenz(a)anthracene (DMBA) induced rat mammary tumour is inhibited by the bioflavonoid quercetin (10(-4) M). By partial purification on a DEAE Cellulose column it was shown that the quercetin-inhibitable enzyme activity can be eluted in a separate peak which contains markedly reduced cAMP-dependent protein kinase activity. Since quercetin does not affect the cAMP-dependent protein kinase activity, this drug becomes a potent tool for the quantitation of this special activity in the tumor. By hormonal manipulation, namely ovariectomy and estrogen treatment, it was shown that changes in the growth rate of the tumour were closely correlated with the magnitude of these special protein kinase activities. These results suggest a possible cause-and-effect relationship between cyclic AMP-independent protein kinase activity and tumour malignancy in this chemically induced tumor. These data are similar to recent findings in viral-induced malignant transformation.
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PMID:cAMP-independent protein kinase activity is correlated with growth of rat mammary tumors. 632 87

The abilities of cyclic adenosine 3':5'-monophosphate (cAMP) and cyclic 8-azidoadenosine 3':5'-[32P]monophosphate (8-N3-[32P]cAMP) to bind to the regulatory subunit (RII) of the type II cAMP-dependent protein kinase isozyme and to cause subsequent dissociation of the holoenzyme were compared in extracts from adult and neonatal mouse lung and lung adenoma. RII in extracts from adult lung exhibits equal numbers of high- (Kd 15 nM) and low- (Kd 230 nM) affinity 8-N3-[32P]cAMP binding sites. In the neonate, the proportion of high-affinity sites is reduced to 20% while, in lung adenoma, only low-affinity RII binding is observed. Low-affinity RII binding is correlated with an inability of cAMP to dissociate the type II holoenzyme completely. Sucrose gradient sedimentation of adult lung cytosol in the presence of cAMP shows complete dissociation of the type I isozyme, while only some of the type II holoenzyme is dissociated. This is in contrast to the case with lung tumor cytosol, in which only low-affinity binding is observed and no apparent dissociation of the type II isozyme occurs. cAMP does promote RII dephosphorylation within the holoenzyme, however, suggesting that cAMP can bind to RII without dissociating the tetramer. Consistent with this interpretation, photoincorporation of 8-N3-[32P]cAMP prior to sucrose gradient sedimentation results in the formation of a photolabeled RII complex which sediments at the same rate as does the holoenzyme. Two-dimensional gel electrophoresis of RII photolabeled at low and high concentrations of 8-N3-[32P]cAMP suggests that these altered binding and dissociation characteristics of the type II isozyme are not due to the presence of a structurally altered RII molecule. After DEAE-cellulose chromatography of lung cytosol, only high-affinity RII binding is observed, and all of the RII can now be dissociated with cAMP. Low-affinity binding may thus reflect either an altered conformational state of RII or the interaction of the type II kinase with other cytosolic molecules which can affect RII binding and dissociation without altering the functional properties of the type I isozyme.
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PMID:Functional changes in the regulatory subunit of the type II cyclic adenosine 3':5'-monophosphate-dependent protein kinase isozyme during normal and neoplastic lung development. 632 22

We used co-cultures of porcine ovarian granulosa cells and mouse adrenocortical tumor cells (Y-1) to examine the kinetics of contact-dependent intercellular signal transfer and to assess the molecular mechanisms employed by this process. Exposure to follicle-stimulating hormone (FSH) caused cAMP-dependent protein kinase dissociation in granulosa cells and, with time, in Y-1 cells if, and only if, they contacted a responding granulosa cell. Y-1 cells close to a granulosa cell but not touching it failed to respond similarly. In reciprocal experiments, co-cultures were stimulated with adrenocorticotropic hormone (ACTH). Y-1 cells dissociated protein kinase as did granulosa cells in contact with Y-1 cells; however, granulosa cells that were not in contact with Y-1 cells failed to respond to the hormone. Fluorogenic steroids were secreted by Y-1 cells cultured alone and stimulated with ACTH, but were not secreted by cultures exposed to FSH. Neither hormone caused fluorogenic steroid production by granulosa cells. On the other hand these steroids were secreted in co-cultures stimulated with ACTH and to a lesser degree in co-cultures exposed to FSH. Autoradiography revealed that I125-FSH bound only to granulosa cells, never to Y-1 cells, even if they were in contact with an ovarian cell. The possibility of cell fusion was tested by experiments in which Y-1 cell membranes were labeled with cationized ferritin. These cells were then placed in co-culture with ovarian granulosa cells that had previously been allowed to ingest latex spheres. At regions of gap junctions between Y-1 and granulosa cells ferritin remained attached to the adrenal cell membrane and was never observed to migrate to the granulosa cell membrane. From these data, we conclude that hormone specific stimulation of one cell type leads to protein kinase dissociation in heterotypic partners only if they contact a hormone responsive cell. This signal transfer is bidirectional, exhibits temporal kinetics and occurs in the absence of apparent cell fusion. The only structural feature connecting Y-1 and granulosa cells were gap junctions implying they provided the communication channels; however, alternative mechanisms cannot be excluded. We have not established the identity of the signal being transferred although cAMP is a logical candidate.
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PMID:Hormone-induced intercellular signal transfer dissociates cyclic AMP-dependent protein kinase. 632 20

In order to test for biologically valid, direct communication between mouse adrenal tumor and porcine ovarian granulosa cells a method was needed for distinguishing the two cell types in culture. To this end granulosa cells were cultured for 24-48 hours after which they were challenged with rhodamine conjugated latex beads for 30 minutes to 24 hours in monolayer culture. When phagocytosis was allowed to occur for longer than one hour the phagocytic vesicles containing the conjugated beads appeared to fuse with each other and with digestive vacuoles. The resultant vesicles contained many beads and were located within the cell body close to the nucleus. At shorter incubation periods, beads were observed predominantly in the periphery of the cell. Y-1 adrenal cortical tumor cells failed to ingest beads and could be distinguished from the bead labeled granulosa cell in coculture with scanning or thin section electron microscopic as well as fluorescence microscopic techniques. Gap junctions were observed between heterotypic cell pairs; however, no evidence of cell fusion was found. ACTH stimulated granulosa: Y-1 adrenal cocultures initiated cAMP-dependent kinase dissociation in the Y-1 cells and in contacting granulosa cells identified positively by the presence of the beads. We have used the bead labeling technique and a procedure for following the kinetics of cAMP-dependent protein kinase dissociation in order to follow the specific hormonal stimulation of these heterotypic cells in coculture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multiparameter morphology as a means of specifically identifying hormone stimulated adrenal cortical tumor cells (Y-1) and granulosa cells in coculture. 633 Aug 79

Certain metabolic properties of hormonally responsive osteogenic sarcoma cells derived from a transplantable rat tumor have been compared with those of related normal rat bone cells. All studies were carried out on cells grown in monolayer culture. Normal rat bone cells derived by repeated collagenase/trypsin digestion of newborn rat calvaria. Bone cells selected for comparison were thought to be osteoblast-like, as judged by enrichment of alkaline phosphatase and adenylate cyclase responsiveness to parathyroid hormone and prostaglandin E2. The adenylate cyclases of the two cell strains were similarly stimulated by a range of prostanoids and their metabolites and analogs. Morphology showed the two cell strains to be similar; the only obvious difference was a multilayering of cells in the sarcoma cultures, while the normal cultures showed abundant extracellular fibril formation which was not seen in the tumor cells. Investigation of the cAMP-dependent protein kinase isoenzymes showed the presence of two forms in both cell types, one eluting at a low salt concentration and the other at a high salt concentration. There was approximately twice the amount of the first isoenzyme compared to the second isoenzyme. The results indicate the usefulness of the two cell strains to elucidate further the molecular mechanisms of action of parathyroid hormone and prostaglandins.
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PMID:Functional properties of hormonally responsive cultured normal and malignant rat osteoblastic cells. 693 60

The molecular species of cyclic adenosine 3':5'-monophosphate (cAMP) receptor proteins (high-affinity-binding proteins) present in hormone-dependent and -independent rat mammary carcinomas were identified and characterized. Three major types of cAMP receptor proteins, with molecular weights of 39,000, 48,000, and 56,000, specifically incorporated the photoaffinity label, 8-azido-cyclic adenosine 3':5'-[32P]monophosphate and were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the tumor cytosols. The M.W. 48,000 and 56,000 receptor proteins appeared to be the regulatory subunits of cAMP-dependent protein kinase types I and II, respectively, and the M.W. 39,000 receptor protein was the proteolytic fragment of the M.W. 56,000 receptor protein. The relative amounts of these cAMP receptor proteins varied from one tumor type to another and showed no correlation with respect to the hormone dependency of tumors. Under two-dimensional gel electrophoresis, however, the M.W. 56,000 receptor protein from hormone-dependent tumors migrated as a doublet and shifted to either a more acidic or more basic charge than that of the receptor protein of hormone-dependent tumors. The alteration of the charge of the receptor did not affect the affinity for cAMP binding, because both hormone-dependent and hormone-independent tumor cytosols exhibited the dissociation constant for cAMP of approximately 10(-8) M. The M.W. 56,000 cAMP receptor protein from hormone-dependent tumors exhibited self-phosphorylation, but that from hormone-independent tumors did not. The diethylaminoethyl cellulose elution profiles of cAMP receptor proteins also differed between hormone-dependent and -independent tumors; cAMP binding activity from hormone-dependent tumors coeluted with cAMP-dependent protein kinase activity, whereas most of the cAMP binding activity from hormone-independent tumors eluted at a higher ionic strength than did cAMP-dependent protein kinase activity. These results suggest that the charge alteration of cAMP receptor proteins, which appears to occur at a site remote from that of cAMP binding, may be associated with the hormone independency of mammary tumors.
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PMID:Cyclic adenosine 3':5-monophosphate receptor proteins in hormone-dependent and -independent rat mammary tumors. 721 51

The direct effect of omega-3 and omega-6 fatty acids on the proliferation of mouse mammary tumor cells (MTC) was examined in a serum-free cell culture system. While the EGF-induced proliferation of normal mammary epithelial cells was shown to be enhanced by omega-3 and omega-6 fatty acids and prostaglandins (PGs), a majority (75-80%) of primary mammary tumors were not stimulated by these agents. Compared to normal cells, some MTC cultures showed a higher susceptibility to inhibition by omega-3 fatty acids. The general lack of response of MTC cultures to PGE2 and cyclic adenosine monophosphate (cAMP) suggests some alterations in the cAMP-mediated pathway. However, the PGE2-induced cAMP levels and cAMP-dependent protein kinase (PKA) activities in the tumor cells were comparable to normal cells. We conclude that the proliferation of mammary tumor cells either follow a cAMP-PKA-independent pathway or have some alterations in the serine/threonine kinase mediated signaling pathway.
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PMID:Omega-3 and omega-6 fatty acids and PGE2 stimulate the growth of normal but not tumor mouse mammary epithelial cells: evidence for alterations in the signaling pathways in tumor cells. 753 35

Expression of the RI alpha subunit of cAMP-dependent protein kinase type I is enhanced in human cancer cell lines, in primary tumours, in cells after transformation and in cells upon stimulation of growth. We have investigated the effect of sequence-specific inhibition of RI alpha gene expression on in vivo tumour growth. We report that single injection RI alpha antisense treatment results in a reduction in RI alpha expression and inhibition of tumour growth. Tumour cells behaved like untransformed cells by making less protein kinase type I. The RI alpha antisense, which produces a biochemical imprint for growth control, requires infrequent dosing to halt neoplastic growth in vivo.
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PMID:A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth. 758 18


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