Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic AMP (cAMP) analogues that selectively bind to either one of the two binding sites of cAMP-dependent protein kinase demonstrate a potent inhibition of the growth stimulated by estrogen in MCF-7 human breast-cancer cells in culture. The site-selective analogues, which are more potent activators of protein kinase than the analogues studied earlier, exhibit growth inhibition at micromolar concentrations. Among the analogues tested, 8-Cl-cAMP (Site I-selective) and N6-benzyl-cAMP (Site 2-selective) are the 2 most potent inhibitors, causing 40-70% inhibition of the estrogen-stimulated growth at 10-20 microM concentrations with no sign of toxicity. 8-Cl-cAMP (1 microM) in combination with N6-benzyl-cAMP (0.5 microM) almost completely blocks estrogen-stimulated growth, demonstrating synergism between the Site 1- and Site 2-selective analogues. The growth inhibition parallels an increase in the R11 cAMP receptor protein with a decrease in the R1 receptor as well as reduction of c-myc and c-ras oncoproteins, whereas growth inhibition by tamoxifen does not affect the levels of the cAMP receptor proteins or the c-myc and c-ras protein levels. Site-selective cAMP analogues are antagonistic to estrogen stimulation of breast-cancer cell growth through a mechanism different from that of tamoxifen.
Int J Cancer 1988 Jun 15
PMID:Site-selective cyclic AMP analogues are antagonistic to estrogen stimulation of growth and proto-oncogene expression in human breast-cancer cells. 283 20

This study deals with the effect of four types of COOH-terminal cholecystokinin (CCK) fragments on the growth of xenotransplantable human gastric cancer (SC-6-JCK, a poorly differentiated adenocarcinoma) whose growth has been promoted by pentagastrin. The growth of the tumor was inhibited using daily s.c. injections of CCK-octapeptide (CCK-8) and glutaryl-CCK-8 at a dose of 500 micrograms/kg body weight. After 30 days of treatment with CCK-8 or glutaryl-CCK-8, a significant decrease was observed in the tumor weight (P less than 0.05) and the tumor size P less than 0.01) in comparison with those of the control. But treatment with CCK-12 and pyroglutamyl-CCK-8 did not produce inhibition of tumor growth. Furthermore the correlation between the effect of CCK-8 on the normal rise in tumor cyclic adenosine 3':5'-monophosphate (cAMP) levels caused by pentagastrin injection and tumor growth was studied. The increase of cAMP by a single i.p. injection of pentagastrin at a dose of 20 micrograms/mouse was significantly inhibited by pretreatment with CCK-8 at concentrations equimolar to pentagastrin (P less than 0.05), while cAMP in the tumor was slightly elevated by a single i.p. injection of CCK-8 alone. Also in the in vitro study, CCK-8 inhibited the increase of cAMP and the activation of cAMP-dependent protein kinase which was stimulated by pentagastrin. These results suggest that proliferation of gastrin-dependent human gastric cancers may be suppressed by CCK in competition with gastrin.
Cancer Res 1986 Feb
PMID:Cholecystokinin inhibition of tumor growth and gastrin-stimulated cyclic adenosine 3':5'-monophosphate metabolism in human gastric carcinoma in nude mice. 300 May 84

A human gastric carcinoma cell line TMK-1 was established in vitro by the soft agar method from SC-6-JCK, a poorly differentiated adenocarcinoma xenotransplanted in nude mice. TMK-1 cells had a doubling time of approximately 35 hr and showed carcinoembryonic antigen (CEA), alpha 1-antitrypsin and secretory component immunoreactivity. Ultrastructurally, the tumor cells were characterized by numerous mitochondria, tubulovesicles and intracytoplasmic canaliculi filled with abundant microvilli. The growth of TMK-1 cells was promoted by 10nM human gastrin (G-17), 2 microM tetragastrin or 2 microM pentagastrin, among which human gastrin showed the most effective growth promotion. Moreover, incorporation of [3H]thymidine into TMK-1 cells was stimulated by gastrin in a dose-dependent manner. The content of cyclic adenosine 3',5'-monophosphate (cAMP) in TMK-1 cells was increased by gastrin treatment but decreased to the control level within 10 min. cAMP-dependent protein kinase was also activated by gastrin administration.
Jpn J Cancer Res 1985 Nov
PMID:Growth-promoting effect of gastrin on human gastric carcinoma cell line TMK-1. 300 17

Two-stage carcinogenesis is involved in the transformation of mouse fibroblasts BALB/c 3T3 cells. In order to investigate the role of cyclic adenosine 3':5'-monophosphate (cAMP)-dependent protein kinase at the stage of initiation, the following experiments were carried out: (a) two initiated clones (M14, M20) which exhibit 12-O-tetradecanoylphorbol-13-acetate-dependent growth in soft agar medium were isolated from cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. The activity of cAMP-dependent protein kinase in M14 was reduced while that in M20 was similar to the level in parental cells. However, cAMP-binding activity to a regulatory subunit of cAMP-resistant clones were isolated from 4-nitroquinoline oxide- or ethyl methanesulfonate-treated cells. These clones have reduced activities in both cAMP-binding and cAMP-dependent protein kinase itself. Two of three cAMP-resistant clones were proved to be able to grow in soft agar medium only in the presence of 12-O-tetradecanoylphorbol-13-acetate.
Cancer Res 1987 Feb 15
PMID:Defects of cyclic adenosine 3':5'-monophosphate-dependent protein kinases in initiated clones derived from BALB/c 3T3 mouse fibroblasts. 302 23

We have compared the properties of cyclic adenosine 3':5'-monophosphate (cAMP)-dependent protein kinases I and II in hormone-dependent/cAMP-sensitive (DMBA tumor) and hormone-independent/cAMP-resistant (DMBA 1 tumor) rat mammary carcinomas. cAMP-resistance was not due to less total kinase in the hormone-independent tumor, grossly altered distribution between soluble and particulate forms of the kinase (80% soluble in either tumor), alteration in the relative proportion of isozymes I and II of the protein kinase (the soluble and the particulate fraction from both tumors contained about 50% of either isozyme), or a decreased sensitivity towards cAMP (both isozymes had affinities for cAMP and its derivatives that corresponded closely with those of isozymes from normal tissues). Furthermore, the sensitivity of the enzymes towards thermal denaturation was identical for samples from the two tumor types. Subtle differences did, however, exist between the regulatory moieties [regulatory subunit of cAMP-dependent protein kinase II (RII)] of isozyme II from the two tumors: autophosphorylated RII from the hormone-independent tumor migrated as a doublet corresponding to Mrs 54,000 and 52,000 on sodium dodecyl sulfate-polyacrylamide gels, against Mrs 53,000 and 52,000 for RII from the hormone-dependent tumor; RII from the two tumors showed different elution profiles upon DEAE-cellulose chromatography; a considerable proportion of the soluble RII in the hormone-independent tumor formed supramolecular aggregates as judged by size-exclusion chromatography. No such microheterogeneity was noted for isozyme I. This study thus shows that the lack of cAMP-responsiveness of one tumor is related either to a defect distal to the cAMP-dependent protein kinases or to the appearance of the new subtype of RII in the resistant tumor. If the latter explanation is correct, it means that the part of the RII molecule responsible for interaction with other proteins rather than that responsible for cAMP-binding and control of protein kinase activity modulates the growth-inhibiting response to cAMP.
Cancer Res 1987 May 15
PMID:Characterization of the cyclic adenosine 3':5'-monophosphate effector system in hormone-dependent and hormone-independent rat mammary carcinomas. 303 9

Dibutyryl cyclic adenosine 3':5'-monophosphate (Bt2cAMP) and beta-all-trans retinoic acid (RA) have been shown separately, and in some cases in combination, to modulate the growth, differentiation, and cAMP-dependent protein kinase (PK-A) activity of various tumor cells. The effects of Bt2cAMP and RA on a cholinergic clone (S20) of C1300 mouse neuroblastoma cells were explored in the present study. Treatment of these cells with 1 mM Bt2cAMP for 3 or more days resulted in 93% inhibition of cell proliferation in monolayer cultures and in 98% inhibition of colony formation in semisolid medium (0.5% agarose). In contrast, treatment of the cells with 1 or 10 microM RA had no inhibitory effects on cell proliferation in monolayer cultures but enhanced colony formation in agarose by up to 130%. The growth of cells treated with a combination of Bt2cAMP and RA was inhibited, although less so than with Bt2cAMP alone. Cells treated with Bt2cAMP alone or Bt2cAMP and RA extended long, neurite-like, cellular processes indicative of differentiation, whereas only a few untreated or RA-treated cells produced such extensions. The amount of [3H]cAMP-binding protein increased gradually up to 2-fold during a 3-day treatment with Bt2cAMP; in contrast it decreased by nearly 2-fold during RA treatment. These changes occurred in the level of the type I regulatory subunit (RI) of PK-A as determined by photoaffinity labeling with 8-azidoadenosine cyclic 3':5'-[32P]monophosphate. The increase in RI following Bt2cAMP treatment was corroborated by DEAE-cellulose chromatography. This analysis also demonstrated that type I PK-A is the predominant kinase in the untreated S20 cells and that RI exists as a free subunit in Bt2cAMP-treated cells. The activity of PK-A decreased by about 20% following treatment with either Bt2cAMP or RA and by 45% following treatment with a combination of both agents. These results suggest that the distinct effects of Bt2cAMP and RA on the anchorage-independent growth of S20 cells may be related to their opposite effects on the level of RI.
Cancer Res 1987 May 01
PMID:Differential effects of dibutyryl cyclic adenosine monophosphate and retinoic acid on the growth, differentiation, and cyclic adenosine monophosphate-binding protein of murine neuroblastoma cells. 303 22

We have shown previously that a prominent early signal in the phorbol-12-myristate-13-acetate (PMA) effect on leukemic cells as well as on other malignant cells is a rapid and dramatic increase in the turnover of phosphate in a Mr 17,000 to 20,000 cytosolic protein and a moderate increase in turnover of phosphate in a Mr 27,000 protein, as detected in the intact cells by 2-dimensional gel electrophoresis. To further elucidate the mechanism of this phosphorylation event, we have examined the protein kinases which can reconstitute this event in a cell-free system. Activation of the endogenous Ca2+-activated phospholipid-dependent protein kinase (Ca-PL-PK) as well as addition of purified Ca-PL-PK to the cytosol of HL-60 leukemic cells resulted in enhanced phosphorylation of phosphoprotein Mr 27,000 (PP27) but did not affect the phosphorylation of phosphoprotein Mr 17,000 to 20,000 (PP17-20). In contrast, PP17-20 was heavily phosphorylated under cell-free conditions by the catalytic subunit of cAMP-dependent protein kinase (cAMP-PK). Exposure of intact cells to dibutyryl-cAMP resulted in increased phosphorylation of PP17-20. These conditions also enhanced the phosphorylation of PP27, showing that PP27 can act as a substrate for both Ca-PL-PK and cAMP-PK under cell-free conditions. Tryptic digest analysis of PP17-20 showed that one of four phosphopeptides is preferentially phosphorylated in PMA-induced PP17-20. An additional phosphopeptide was phosphorylated in cAMP-PK-catalyzed PP17-20. Thus, cAMP-PK alone mimics the effect of PMA on phosphorylation of PP17-20, but it introduces additional modifications. The precise role of this kinase in PMA-induced phosphorylation of PP17-20 remains to be clarified. We found further that enhanced phosphorylation of PP17-20 is also associated with malignant transformation of NIH/3T3 cells transformed by V-rasKi oncogene of Kirsten sarcoma virus. The tryptic phosphopeptide map of PP17-20 (phosphorylated in vivo) in the transformed cells was similar to that of PP17-20 in PMA-treated HL-60 cells but not to that induced by cAMP-PK, suggesting that the process activated by PMA which leads to phosphorylation of PP17-20 resembles an intrinsic cellular process which is enhanced in certain malignant cells.
Cancer Res 1985 Jul
PMID:Cell-free system studies on the phosphorylation of the 17,000-20,000 dalton protein induced by phorbol ester in human leukemic cells and evidence for a similar event in virally transformed murine fibroblasts. 315 76

The synthetic thioether phospholipid BM 41.440 (1-S-hexadecyl-2-methoxymethyl-rac-glycero-3-phosphocholine) was found to inhibit protein kinase C (PKC) activity competitively with respect to phosphatidylserine, with an apparent Ki value of about 6.4 microM. The agent also inhibited the enzyme activated by diolein or 12-O-tetradecanoylphorbol-13-acetate (TPA), without affecting binding of [3H]phorbol-12,13-dibutyrate to the enzyme. Myosin light chain kinase and cAMP-dependent protein kinase were not inhibited by BM 41.440, indicating a specificity of the action of the agent. BM 41.440 partly blocked the TPA-induced depletion of soluble PKC in HL60 and KG-1 cells (responsive to the differentiating effect of TPA) but not in K562 cells (resistant to the TPA effect). The thioether inhibited the phosphatidylserine/Ca2+-dependent phosphorylation of several common proteins in the solubilized homogenates of HL60 and KG-1 cells, and that of apparently distinct proteins in the preparation of K562 cells. The TPA-induced differentiation of HL60 and KG-1 cells was inhibited by BM 41.440 at a concentration inhibitory to PKC, but differentiation of HL60 cells promoted by dimethyl sulfoxide, retinoic acid, and 1,25-dihydroxyvitamin D3, on the other hand, was not affected. The present data suggested that PKC inhibition might partly account for the antineoplastic effect of BM 41.440, and that the agent could be useful in studying involvements of the PKC system in cellular processes.
Cancer Res 1988 Dec 01
PMID:Effects of thioether phospholipid BM 41.440 on protein kinase C and phorbol ester-induced differentiation of human leukemia HL60 and KG-1 cells. 318 76

Differential expression of type I and type II cAMP-dependent protein kinase isozymes has been linked to growth regulation and differentiation. We examined the expression of protein kinase isozymes in the LS 174T human colon cancer cell line during 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP)-induced growth inhibition. Two species of RII (the regulatory subunit of protein kinase type II) with apparent Mr 52,000 (RII52) and Mr 56,000 (RII56) and a single species of RI (the regulatory subunit of protein kinase type I) with Mr 48,000 were identified in the cancer cells. RI and both forms of RII were covalently labeled with 8-azidoadenosine 3',5'-cyclic [32P]monophosphate, and two anti-RII antibodies that exclusively recognize either RII52 or RII56 resolved two forms of the RII receptors. 8-Cl-cAMP treatment induced a decrease of RI and an increase of both RII52 and RII56 in the cytosols of cancer cells and rapid translocation (within 10 min) of RII52 from the cytosol to nucleus. 8-Cl-cAMP caused transcriptional activation of the RII52 receptor gene and inactivation of the RI receptor gene. It also exhibited high-affinity site-1-selective binding to the purified preparations of both RII receptor proteins. Thus, differential regulation of various forms of cAMP receptor proteins is involved in 8-Cl-cAMP-induced regulation of cancer cell growth, and nuclear translocation of RII52 receptor protein appears to be an early event in such differential regulation.
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PMID:Selective modulation of protein kinase isozymes by the site-selective analog 8-chloroadenosine 3',5'-cyclic monophosphate provides a biological means for control of human colon cancer cell growth. 341 98

Many lysosomal hydrolases in cases of human cancer were found to be accompanied by acidic variant forms together with the major hydrolase components. Such variants were found to be phosphorylated not only at their carbohydrate moiety which contributes largely to their acidic property, but also at the protein moiety. We identified a cAMP-dependent protein kinase which is responsible for phosphorylation of arylsulfatase B. The protein kinase activity toward the sulfatase was considerably higher in transplanted lung cancer than in normal lung in the presence of cAMP. The B enzyme purified from normal human liver was found to contain 0.6mol of Pi/mol of B enzyme, and protein kinase treatment added a further 1.3mol Pi to give a single phosphopeptide (X) containing phosphothreonine. On the other hand, the B1 enzyme purified from transplanted human lung cancer which had been labeled in vivo with [32P] Pi revealed at least two phosphopeptides (X and Y). Assuming that the sulfatase from liver and lung cancer possesses the same number of available phosphorylation sites, phosphorylation of site X (Thr) which is available only by deliberate phosphorylation of the native, ordinary B enzyme, appears to be cancer-associated. Increased phosphorylation of the sulfatase resulted in a maximum 50% elevation in arylsulfatase activity, followed by a decrease in the activity upon overphosphorylation, using an artificial substrate.
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PMID:[Phosphorylation of lysosomal hydrolases in human cancer and its significance]. 360 35


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