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)

Protein Kinase C (PKC) has been a principal regulatory enzyme whose function has been intensely investigated in the past decade. The primary features of this family of enzymes includes phosphorylation of serine and threonine residues located on basic proteins and peptide in a manner that is stimulated by calcium, phospholipid, and either diacylglycerol or phorbol esters. An additional intriguing feature of the enzymes is its ability to form two membrane-associated states, one of which is calcium dependent and reversible and the second is an irreversible complex which has the characteristics of an intrinsic membrane protein. Formation of the irreversible membrane-bound form is greatly facilitated by calcium and the tumor-promoting phorbol esters but does not appear to include covalent changes in the PKC structure. The intrinsic membrane-bound form is a very different enzyme in that its activity is no longer dependent on the other cofactors. It is proposed that formation of the irreversible membrane-bound form may be a mechanism for generating long-term cell regulation events where transient cell signals and second messengers induce long-term changes in the distribution of an enzyme in the cell. This property may be common to a number of regulatory proteins that are known to be distributed between the cytosol and membrane-fractions in the cell. Unfortunately, many problems have confronted study of PKC mechanism using the in vitro assay. This assay involves aggregation of the substrate, phospholipid, and enzyme to form a discontinuous mixture. Such a complex system prevents straightforward interpretation of enzyme kinetic data. Although many compounds affect the in vitro activity of PKC, most appear to accomplish this by relatively uninteresting mechanisms such as interference with the aggregation process. While some highly potent inhibitors undoubtedly interact directly with PKC, they also inhibit other enzymes and there are no entirely specific inhibitors of PKC known. Speculation on the possible roles of PKC in cell regulation are abundant and exciting. However, delineation of the regulatory roles of PKC may require another decade of intense effort.
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PMID:Activation and regulation of protein kinase C enzymes. 201 Apr 34

In this report, point mutations of the K-ras gene at codon 146 were analyzed in 25 cases of colon cancer, 4 cases of lung cancer, and 41 cases of lymphoid malignancy. A codon 146 mutation substituting threonine (ACA) for alanine (GCA) was detected in the tumor tissue of a patient with colon cancer and was not detected in the normal tissue of the same patient. Any additional mutations of the ras gene family were not detected in this patient. These results suggest that the codon 146 mutation of the K-ras gene could be involved in the development of naturally occurring human malignancies.
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PMID:A novel point mutation at codon 146 of the K-ras gene in a human colorectal cancer identified by the polymerase chain reaction. 201 78

Protein kinase C (PKC) is a Ca2(+)- and phospholipid-dependent serine and threonine protein kinase which binds and is activated by tumor promoters such as the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA). PKC can be activated in vitro by phosphatidylserine (PS) plus Ca2+. We report here that the compound fecapentaene-12 can replace the requirement for PS in the activation of PKC by Ca2+. In addition, at low concentrations fecapentaene-12 can enhance the activation of PKC by Ca2+ and PS. It can also either enhance or inhibit activation of PKC by the tumor promoter teleocidin, depending on the assay conditions. These results are of interest since fecapentaene is known to be a potent mutagen that is produced by Bacteroides species present in the lumen of the human colon. The present studies raise the possibility that this compound might also play a role in colon cancer by altering the activity of PKC.
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PMID:Effects of a fecapentaene on protein kinase C. 201 37

At least two different types of proteins, NF-kappa B/KBF1 and HIV-EP1/PRDII-BF1/MBP-1, which are members of a family of rel oncoproteins and metal-finger proteins, respectively, bind to the human immunodeficiency virus type (HIV-1) enhancer. As a new member of a HIV-EP1 family that is expressed at a high level in T cells, we have isolated cDNA clones of HIV-EP2 by cross-hybridization with HIV-EP1 cDNA. HIV-EP2 protein consists of 1,833 amino acids and has a molecular weight of 211,000. HIV-EP2 protein is highly homologous with HIV-EP1/PRDII-BF1/MBP-1 in three regions. These three regions contain the potential nuclear localization signal followed by a Ser/Thr-rich region, the DNA-binding domain consisting of a metal-finger structure, and a cluster of acidic amino acids. The DNA-binding property of HIV-EP2 was similar to that of HIV-EP1. Northern blot analysis of HIV-EP2 mRNA indicated relatively high expression in the T cell line Molt-4 and in some tumor cell lines. Furthermore, like HIV-EP1, expression of HIV-EP2 mRNA was greatly induced by mitogen and phorbol ester treatment of Jurkat T cells, suggesting that HIV-EP2 acts in HIV production from latently infected T cells.
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PMID:HIV-EP2, a new member of the gene family encoding the human immunodeficiency virus type 1 enhancer-binding protein. Comparison with HIV-EP1/PRDII-BF1/MBP-1. 202 70

Extensive biochemical studies have shown that mucin tumor antigens have a range of molecular sizes from 200 to greater than 1000 kDa. The molecular size of mucin antigens can be dramatically affected by the source and method of purification. Mucin antigens vary from 24 to 80% in carbohydrate content and their density is usually greater than 1.40 g/ml. Galactose and N-acetyl glucosamine are the predominant sugar residues in many mucins, whereas mannose is usually present in low levels or absent. The amino acids serine, threonine, alanine, glycine, and proline are abundant in mucins. An O-glycosidic linkage between the carbohydrate and protein of mucins is the most common linkage encountered. The gene encoding the core peptide for at least one mucin tumor marker, HMFG, has been identified, sequenced, and expressed. These findings may lead to a better understanding of the multiepitope nature of mucin tumor markers. The advent of hybridoma technology has yielded several monoclonal antibodies that have been used to identify the presence of tumor-associated mucins in the sera of cancer patients. Elevated levels of mucin antigens have been found in the serum of most patients with advanced adenocarcinomas. Many studies have shown that tumor-associated markers are useful in monitoring patients following cancer treatment. Clinically useful immunoassays have been developed for monitoring patients with ovarian, breast, and pancreatic adenocarcinomas. Although individual mucin tumor markers show limited utility in detecting early adenocarcinoma, recent studies using multiple mucin markers have suggested that early detection, at sensitivities greater than 50%, can be achieved.
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PMID:Mucin glycoproteins as tumor markers. 210 May 76

The ability of tumor-promoting phorbol diesters to inhibit both insulin receptor tyrosine kinase activity and its intracellular signaling correlates with the phosphorylation of the insulin receptor beta subunit on serine and threonine residues. In the present studies, mouse 3T3 fibroblasts transfected with a human insulin receptor cDNA and expressing greater than one million of these receptors per cell were labeled with [32P]phosphate and treated with or without 100 nM 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). Phosphorylated insulin receptors were immunoprecipitated and digested with trypsin. Alternatively, insulin receptors affinity purified from human term placenta were phosphorylated by protein kinase C prior to trypsin digestion of the 32P-labeled beta subunit. Analysis of the tryptic phosphopeptides from both the in vivo and in vitro labeled receptors by reversed-phase HPLC and two-dimensional thin-layer separation revealed that PMA and protein kinase C enhanced the phosphorylation of a peptide with identical chromatographic properties. Partial hydrolysis and radiosequence analysis of the phosphopeptide derived from insulin receptor phosphorylated by protein kinase C indicated that the phosphorylation of this tryptic peptide occurred specifically on a threonine, three amino acids from the amino terminus of the tryptic fragment. Comparison of these data with the known, deduced receptor sequence suggested that the receptor-derived tryptic phosphopeptide might be Ile-Leu-Thr(P)-Leu-Pro-Arg. Comigration of a phosphorylated synthetic peptide containing this sequence with the receptor-derived phosphopeptide confirmed the identity of the tryptic fragment. The phosphorylation site corresponds to threonine 1336 in the human insulin receptor beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Threonine 1336 of the human insulin receptor is a major target for phosphorylation by protein kinase C. 211 1

We have investigated the anti-metastatic and anti-invasive activities of polypeptide analogues based on the Arg-Gly-Asp (RGD) adhesive signal in fibronectin, poly(RGD), poly(RGDS)[Arg-Gly-Asp-Ser] and poly(RGDT)[Arg-Gly-Asp-Thr]. These polypeptides containing repetitive RGD sequences were able to inhibit experimental and spontaneous lung metastases of B16-BL6 cells more effectively than the corresponding monomer peptides. In the spontaneous metastasis model, multiple i.v. administrations of these polymeric peptides before or after surgical excision of the primary tumor resulted in a significant reduction of lung tumor colonies. However, there was no significant difference in ability to inhibit spontaneous lung metastasis among poly(RGD), poly(RGDS) and poly(RGDT), although the carboxy-terminal amino acid residue (i.e., Xaa in -RGDXaa-) has been shown to play an important role in the expression of cell adhesive character. The treatment with poly(RGD) substantially prolonged the survival time for mice injected s.c. with B16-BL6 melanoma as compared with the untreated control. We also found that the polypeptides were potently able to inhibit the invasion and migration of tumor cells in vitro. Since these polypeptide analogues showed no antigenicity in the host and had no toxic effect on tumor cells in vitro, they may be potentially useful in the prevention of cancer metastasis.
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PMID:Anti-metastatic and anti-invasive effects of polymeric Arg-Gly-Asp (RGD) peptide, poly(RGD), and its analogues. 211 67

Talin is a high molecular weight phosphoprotein that is localized at adhesion plaques. We have found that talin phosphorylation increases 3.0-fold upon exposure of chicken embryo fibroblasts to the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate. Talin isolated from tumor promoter-treated cells is phosphorylated on serine and threonine residues. Vinculin, a 130 kDa talin-binding protein, also exhibits increased phosphorylation in vivo in response to tumor promoter, but to a lesser degree than does talin. Because tumor-promoting phorbol esters augment protein kinase C activity, we have compared the ability of purified protein kinase C to phosphorylate talin and vinculin in vitro. Both talin and vinculin were found to be substrates for protein kinase C; however, talin was phosphorylated to a greater extent than was vinculin. Cleavage of protein kinase C-phosphorylated talin by the calcium-dependent protease (Type II) revealed that while both the resulting 190-200 and 46 kDa proteolytic peptides were phosphorylated, the majority of label was contained within the 46-kDa fragment. Although incubation of chicken embryo fibroblasts with tumor-promoting phorbol ester induces a dramatic increase in talin phosphorylation, we detected no change in the organization of stress fibers and focal contacts in these cells. Exposure of the cells to tumor promoter did, however, result in a loss of actin and talin-rich cell surface elaborations that resemble focal contact precursor structures.
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PMID:The adhesion plaque protein, talin, is phosphorylated in vivo in chicken embryo fibroblasts exposed to a tumor-promoting phorbol ester. 212 21

In view of the critical role that the Ca2+- and phospholipid-dependent enzyme protein kinase C (PKC) plays in mediating proliferative responses to a number of growth factors, hormones, and tumor promoters, it is thought that selective PKC inhibitors may provide a new class of antiproliferative drugs. Established PKC inhibitors include three major classes of agents: agents that compete with the substrate ATP, agents that compete with the protein substrate, and agents that both compete with ATP and interact with the cofactor phosphatidylserine (PS). In this report, we have characterized the interactions between PKC and N-myristyl-Lys-Arg-Thr-Leu-Arg, a myristylated analogue of a synthetic peptide substrate of PKC. We determined that the myristylated peptide was a novel PKC inhibitor that interacted with PS as well as competed with the protein substrate of PKC. The inhibitory activity of the peptide was conferred by myristylation. We found that the myristylated peptide antagonized Ca2+- and PS-activated PKC with an IC50 of 75 microns, whereas the nonmyristylated peptide lacked this inhibitory activity. A fully active, Ca2+- and PS-independent catalytic fragment of PKC can be generated by limited proteolysis. Although the myristylated peptide was a very poor PKC substrate, this peptide inhibited the catalytic fragment of PKC by apparent competition with the phosphoacceptor substrate histone IIIS with an IC50 of 200 microM, whereas the nonmyristylated peptide showed no inhibitory activity against the catalytic fragment. Thus, the myristylated peptide may serve as a model for the development of selective PKC inhibitors, because its inhibitory mechanism exploits the substrate specificity of PKC, as well as the novel regulation of the enzyme. Furthermore, since endogenous PKC substrates include acylated proteins, the observations that we report here concerning a myristylated synthetic peptide suggest that acylation of proteins may be important in the regulation of PKC activity in vivo.
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PMID:N-myristyl-Lys-Arg-Thr-Leu-Arg: a novel protein kinase C inhibitor. 215 82

The polyoma virus medium and small tumor antigens, as well as simian virus 40 small tumor antigen, form specific complexes with two cellular proteins designated 61- and 37-kDa proteins. In this report, we demonstrate that the 61- and 37-kDa proteins correspond to the A and C subunits, respectively, of the serine- and threonine-specific protein phosphatase 2A (PP2A). On the one hand, antibodies raised against the 61-kDa protein reacted specifically with the purified A subunit of PP2A. Furthermore, the amino acid sequences of seven tryptic peptides from the A subunit were almost identical to sequences of the 61-kDa protein as deduced from the corresponding cDNA sequence. On the other hand, antibodies against the purified C subunit (catalytic subunit) of PP2A reacted specifically with the medium tumor antigen-associated 37-kDa protein. These data suggest a role of PP2A in cell transformation by polyoma virus and simian virus 40.
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PMID:Association of protein phosphatase 2A with polyoma virus medium tumor antigen. 215 2


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