Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cloned Lewis lung carcinoma (LLC) variants were used in an in vitro migration model for dissemination, to determine if prostaglandin E2 (PGE2) produced by nonmetastatic LLC cells could directly stimulate dissemination of metastatic LLC cells and to identify an intracellular mechanism for such an effect. The migration of metastatic LLC clones was stimulated not only by exogenous PGE2 but also by nonmetastatic LLC cells, by their production of a migration-stimulatory factor which was sensitive to indomethacin and anti-PGE2 antibodies. Nonmetastatic LLC clones were unresponsive to migration stimulation by PGE2. The results of in vivo metastasis studies were consistent with those of in vitro migration studies. In vivo lung metastasis was increased by PGE2, as well as by nonmetastatic cells when they were either admixed with the metastatic LLC inoculum, irradiated and injected adjacent to the metastatic LLC tumor, or localized in chambers and implanted s.c. into mice given injections of metastatic LLC cells. Indomethacin blocked metastasis stimulation by nonmetastatic cells. The in vitro PGE2 stimulation of metastatic LLC cells appeared to be linked to a cyclic AMP (cAMP) response, since migration could also be stimulated by dibutyryl-cyclic AMP and blockage of a cAMP response with nicotinic acid ablated the PGE2 stimulation of migration. In vivo metastasis could be stimulated by elevation of cAMP with aminophylline. The differential responsiveness of metastatic versus nonmetastatic LLC cells to PGE2 could not be due to PGE2-adenylate cyclase coupling, since PGE2 increased the cAMP levels in cultures of both metastatic and nonmetastatic LLC cells. There was, however, a difference in the cyclic AMP-dependent protein kinase (PKA) response to PGE2, with PKA activity of metastatic LLC being stimulated by PGE2 and by the adenylate cyclase-stimulator forskolin, whereas PKA of nonmetastatic LLC was not stimulated by these cAMP elevators, suggesting a dysfunction in the cAMP-PKA coupling.
Cancer Res 1990 May 15
PMID:Association of a functional prostaglandin E2-protein kinase A coupling with responsiveness of metastatic Lewis lung carcinoma variants to prostaglandin E2 and to prostaglandin E2-producing nonmetastatic Lewis lung carcinoma variants. 215 67

Protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA) are important for normal cell proliferation. We show that both kinases are down-regulated by a phorbol ester tumor promoter in nontumorigenic murine BALB/c 3T3 fibroblasts (A31 cells), whereas only PKC responded to the phorbol ester in a chemically transformed derivative cell line (DMBA31 cells). In quiescent A31 cells, phorbol dibutyrate (PDBu) caused a 10-fold reduction in PKC activity and a 5-fold reduction in PKA activity. In contrast, PDBu depleted quiescent DMBA31 cells of PKC activity only and had no effect on the PKA activity. In both cell lines, PDBu did not affect the level of PKA regulatory subunits (determined by a cyclic [3H]-AMP binding assay), the levels of mRNA encoding the catalytic and the abundant regulatory subunit (determined by Northern blotting), or the level of the catalytic subunit protein (determined by Western blotting). An in situ gel activity assay confirmed that PDBu reduced the kinase activity of native PKA complexes from A31 cells but not from DMBA31 cells. These results indicate that phorbol esters down-regulate PKA activity by a posttranslational mechanism. They further suggest that the activity of PKC and PKA may be coordinately regulated in nontumorigenic cells and that transformation can disrupt this coordinate regulation.
Cancer Res 1990 Nov 15
PMID:Posttranslational control of cyclic AMP-dependent protein kinase by phorbol ester in normal but not in chemically transformed 3T3 cells. 217 57

Two isoforms of the regulatory subunits of cyclic AMP (cAMP)-dependent protein kinase that bind cAMP are inversely expressed during ontogeny and cell differentiation. These cAMP-binding receptor proteins in harmony may regulate the growth of normal cells and their differentiation into nondividing states. Cancer cells can also be made to differentiate and stop growing when the functional balance of these cAMP receptor proteins is restored by treatment with site-selective cAMP analogues or by the use of an antisense oligodeoxynucleotide, suggesting new approaches to cancer treatment.
Cancer Res 1990 Nov 15
PMID:Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. 222 44

The human cell proliferation-associated nucleolar protein p120 was found in a variety of human cancer specimens but not in most normal resting cells. Polyclonal antibodies raised against bacterially expressed p120 were used to immunoprecipitate the p120 protein isolated from 32P-labeled HeLa cells. The p120 protein was phosphorylated at serine, threonine and tyrosine residues. A tryptic peptide map showed it contained three labeled peptides. One of these peptides comigrated with a p120 peptide phosphorylated in vitro by casein kinase II. This peptide was phosphorylated in vitro both at Ser-181 and Thr-185. This region is juxtaposed to the epitope site recognized by the anti-p120 monoclonal antibody.
 ...
PMID:Phosphorylation of the human cell proliferation-associated nucleolar protein p120. 225 32

In the present study the activities of three different protein kinase were determined in squamous cell carcinoma from the upper aero-digestive tract, and compared with the activities in normal oral mucosa. The protein kinases investigated are: a) cAMP-dependent protein kinase; b) cGMP-dependent protein kinase, and c) casein kinase II. The basal protein kinase activity, when histone IIa was used as substrate, was about 3-fold higher in tumors, as compared to normal mucosa, in the soluble fraction (32.0 +/- 4.2 and 10.9 +/- 2.4 pmol 32P/mg prot. X min, respectively). In the particulate fraction the basal protein kinase activity was about 9 times higher in tumors as compared to normal mucosa (19.4 +/- 5.2 and 2.1 +/- 0.3 pmol 32P/mg prot X min, respectively). The protein kinase activity in the presence of cyclic nucleotide (cAMP/cGMP) minus the basal protein kinase activity was taken as the cAMP- and the cGMP-dependent protein kinase activity, respectively. Maximal protein kinase activity was obtained in the presence of 0.5 microM of cyclic nucleotide both in squamous cell carcinoma and normal mucosa. In the cytosolic fraction the cAMP-dependent protein kinase activity was 33.9 +/- 13.0 pmol 32P/mg prot. X min in tumors, and 28.2 +/- 5.8 pmol 32P/mg prot. X min in normal tissue, after stimulation with 0.5 microM cAMP. The cGMP-dependent protein kinase activity was 5-10% of the cAMP-dependent protein kinase activity, and no concentration-dependent stimulation with cGMP was seen. The cGMP-dependent protein kinase activity in the presence of 0.5 microM cGMP was 2.4 +/- 1.3 and 1.8 +/- 0.6 pmol 32P/mg prot. X min in tumors and normal mucosa, respectively. Casein kinase II activity was determined only in the cytosolic fraction and was found to be 3-fold higher in tumors as compared to normal mucosa (31.8 +/- 5.2 and 8.6 +/- 3.5 pmol 32P/mg prot X min, respectively). This study shows a general increase in histone phosphorylation and casein kinase activity in neoplastic squamous epithelia compared to normal epithelia. No evidence for an increase in cyclic nucleotide dependent protein kinase activities in neoplastic squamous epithelia was found. This study thus supports the idea that phosphorylation/dephosphorylation reactions may play an important role in the control of cell growth, differentiation and proliferation.
Cancer Biochem Biophys 1990 Jul
PMID:Protein kinase activities in neoplastic squamous epithelia and normal epithelia from the upper aero-digestive tract. 226 49

A complementary DNA (cDNA) clone (B4) encoding the catalytic subunit of a cAMP-dependent protein kinase (PKAc) was isolated from a lambda gt10 rat brain cDNA library, using a synthetic oligonucleotide probe whose sequence was based on the known amino acid sequence of a bovine cardiac PKAc. Sequence analysis of this clone revealed a region of 1002 nucleotides which encodes a protein that is 92% homologous to amino acids 17-350 of the bovine cardiac PKAc protein. This clone lacks coding sequences for amino acids 1-16 of the latter protein. Nevertheless, it provided a useful probe to analyze expression of the related gene in a variety of systems. Northern blot analyses using a 32P-labeled probe prepared from a 0.6-kilobase PstI fragment of clone B4 revealed an abundant 4.6-kilobase band in rat brain RNA and lesser amounts of this 4.6-kilobase RNA in rat heart and liver. A 4.6-kilobase RNA was also detected in RNA samples obtained from mouse fibroblasts. This probe also detected homologous RNA in a variety of nonrodent species. In subsequent experiments, this cDNA was used as a probe to elucidate the role of PKAc in post-surgical hepatic regeneration and diethylnitrosamine-induced hepatomas in the rat. These experiments revealed that, following partial hepatectomy, PKAc mRNA is decreased 3-fold by 12 h, returning to normal by 72 h; hepatomas showed no consistent pattern of change in PKAc mRNA levels as compared to controls. Our results indicate that this cDNA encodes an isoform of PKAc which is distinct from PKAc-alpha isolated by Uhler et al. (Proc. Natl. Acad. Sci. USA, 83: 1300-1304, 1986) but highly homologous to PKAc-beta isolated by Showers and Maurer (J. Biol. Chem., 261: 16288-16291, 1986), that depression of cAMP-dependent protein phosphorylation may be an important mechanism in the regeneration of mature rat liver but is not a consistent alteration in chemically induced hepatoma, and that this cDNA is useful as a probe for the study of the role of PKAc gene expression in growth control, particularly in rodent species.
Cancer Res 1990 Mar 15
PMID:Isolation of a complementary DNA encoding the catalytic subunit of protein kinase A and studies on the expression of this sequence in rat hepatomas and regenerating liver. 230 20

A newly synthesized compound, H-87, N-[2-(p-bromo cinnamylmethylamino)ethyl]-5-isoquinolinesulfonamide was found to be a potent and selective inhibitor of cyclic AMP-dependent protein kinase. The effects of H-87 on in vitro sensitivities of various P388 murine leukemia cell lines resistant to several antitumor agents were examined. H-87 significantly potentiated the cytotoxic effects of Adriamycin (ADR), daunorubicin (DAU), vincristine (VCR) and vinblastine (VBL) on P388 cells resistant to these antitumor agents but hardly influenced the effects of mitomycin C (MMC), 5-fluorouracil (5-FU) and cisplatin (CDDP) on ADR-resistant P388 cells (P388/ADR) and P388 phenotypes resistant to the corresponding antitumor agents. H-87 promoted the accumulation of VBL much more in P388/ADR cells than in the sensitive cells by inhibiting the energy-dependent extrusion of the antitumor agent from the cells. These results suggest that this novel isoquinoline-sulfonamide derivative, H-87, overcomes the multidrug resistance by inhibiting the phosphorylation of an outward drug transport system through cyclic AMP-dependent protein kinase.
Cancer Lett 1990 May 15
PMID:Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase, H-87. 233 96

In recent years, we reported the isozyme shift of pyruvate kinase from the M- toward the K-type in human neuroectodermal tumors. To investigate whether this shift enables phosphorylation of pyruvate kinase in these tumors, we studied 29 different specimens of human brain tumors for endogenous pyruvate kinase phosphorylation. While in normal human brain no phosphorylation of pyruvate kinase was detected, in all brain tumors pyruvate kinase became phosphorylated. There was no correlation between the extent of the pyruvate kinase phosphorylation and the histological classification and grading or the pyruvate kinase isozyme composition of the tumors. Only pyruvate kinase type K, and not type M, served as a substrate in the phosphorylation reaction. The phosphorylation of pyruvate kinase could be completely inhibited by addition of fructose 1,6-bisphosphate, a positive effector of pyruvate kinase type K; alanine, however, a negative effector, and phospho-enol-pyruvate, a substrate in the pyruvate kinase reaction, had no effect. While pyruvate kinase type L in liver is phosphorylated by a cyclic AMP-dependent protein kinase, the incorporation of phosphate into pyruvate kinase in human brain tumors appeared to be cyclic AMP independent and occurred exclusively on serine residues.
Cancer Res 1990 Aug 01
PMID:Phosphorylation of pyruvate kinase type K in human gliomas by a cyclic adenosine 5'-monophosphate-independent protein kinase. 236 36

Retention of the vital dyes rhodamine 123 (R-123) and hydroethidine (HET) correlates inversely with the multidrug resistant phenotypes of the adriamycin (ADM)-selected variants of a uv-induced murine fibrosarcoma cell line (UV-2237M). The differential affinity of these dyes for specific cellular organelles makes them unique compounds for studies of cellular transport. HET enters viable cells freely, is dehydrogenated to ethidium bromide (EtBr), and is subsequently accumulated in the nucleus. Viable cells are impermeable to extracellular EtBr, facilitating kinetic analysis of the efflux of intracellular EtBr. We found that the metabolite EtBr was rapidly cleared by ADM-resistant but not by ADM-sensitive cells. R-123 has a high affinity to mitochondria. Our results show that ADM-sensitive cells retain R-123 whereas the ADM-resistant cells do not. The clearance of both R-123 and EtBr from these cells was inhibited by verapamil. Therefore, R-123 and HET may be considered MDR-associated compounds useful in studying the MDR phenotype of cancer cells. Previously we reported a direct correlation between the level of activity of the calcium- and phospholipid-dependent protein kinase (protein kinases C) and ADM resistance in UV-2237M variant lines. In this report, we demonstrate a direct correlation between cellular calcium and MDR in these cells. Although chelation of extracellular calcium by EDTA did not alter the fluorescence profile of R-123 of the various cell lines, treating the ADM-resistant variants with verapamil restored cellular calcium to the same level as that of the parental cells and, at the same time, retarded the facilitated efflux of R-123 and EtBr and partially reversed cancer cell resistance to ADM.
 ...
PMID:Retention of vital dyes correlates inversely with the multidrug-resistant phenotype of adriamycin-selected murine fibrosarcoma variants. 238 29

We investigated the effects of the antiestrogen tamoxifen on MCF-7 cell protein kinase C either by using the in vitro histone kinase assay or by studying the phosphorylation of its endogenous Mr 28,000 protein substrate in intact cells. In the in vitro assay, tamoxifen inhibited the enzyme competitively with respect to phospholipid, whereas estradiol and morpholinobenzyl phenoxy ethanamine, a specific ligand for antiestrogen binding sites, were considerably less efficient. In contrast, tamoxifen did not affect phosphorylation of the Mr 28,000 protein induced by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in intact MCF-7 cells. Estradiol and morpholinobenzyl phenoxy ethanamine also had no effect. At high concentration (100 microM), tamoxifen itself stimulated specific phosphorylation of this Mr 28,000 protein. Estradiol and morpholinobenzyl phenoxy ethanamine neither mimicked nor interfered with this effect. Our data suggest that the effect of tamoxifen on protein kinase C activity depends on the phospholipid environment of the enzyme, and opposite effects may be observed in intact cells to those seen in disrupted cells. The action of tamoxifen on endogenous protein phosphorylation was thought to be due to direct interaction with the phospholipid binding domain of the enzyme rather than by interaction with the estrogen receptor or the antiestrogen binding site. Nevertheless, our results do not rule out a possible activation by tamoxifen of specific protein kinase(s) and phosphatase(s). In any case, the antiproliferative activity of tamoxifen on MCF-7 cells cannot be attributed to its effects on protein kinase C.
Cancer Res 1990 Sep 15
PMID:Opposite effects of tamoxifen on in vitro protein kinase C activity and endogenous protein phosphorylation in intact MCF-7 cells. 239 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>