Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of misfolded proteins in the cell at high temperature may cause entry into a nonproliferating, heat-shocked state. The imino acid analog azetidine 2-carboxylic acid (AZC) is incorporated into cellular protein competitively with proline and can misfold proteins into which it is incorporated. AZC addition to budding yeast cells at concentrations sufficient to inhibit proliferation selectively activates heat shock factor (HSF). We find that AZC treatment fails to cause accumulation of glycogen and trehalose (Msn2/4-dependent processes) or to induce thermotolerance (a protein kinase C-dependent process). However, AZC-arrested cells can accumulate glycogen and trehalose and can acquire thermotolerance in response to a subsequent heat shock. We find that AZC treatment arrests cells in a viable state and that this arrest is reversible. We find that cells at high temperature or cells deficient in the ubiquitin-conjugating enzymes Ubc4 and Ubc5 are hypersensitive to AZC-induced proliferation arrest. We find that AZC treatment mimics temperature up-shift in arresting cells in G1 and represses expression of CLN1 and CLN2. Mutants with reduced G1 cyclin-Cdc28 activity are hypersensitive to AZC-induced proliferation arrest. Expression of the hyperstable Cln3-2 protein prevents G1 arrest upon AZC treatment and temperature up-shift. Finally, we find that the EXA3-1 mutation, encoding a defective HSF, prevents efficient G1 arrest in response to both temperature up-shift and AZC treatment. We conclude that nontoxic levels of misfolded proteins (induced by AZC treatment or by high temperature) selectively activate HSF, which is required for subsequent G1 arrest.
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PMID:Protein misfolding and temperature up-shift cause G1 arrest via a common mechanism dependent on heat shock factor in Saccharomycescerevisiae. 1141 8

The majority of human malignancies have aberrancies in the Retinoblastoma (Rb) pathway. Loss in Rb function results from the phosphorylation and inactivation of Rb by the cyclin-dependent kinases (cdks), main regulators of cell cycle progression. Thus, modulators of cdks may have a role in the treatment of human malignancies. Flavopiridol, the first cdk modulator tested in clinical trials, demonstrates interesting preclinical features: cell cycle block, induction of apoptosis, promotion of differentiation, inhibition of angiogenic processes and modulation of transcriptional events. Initial clinical trials with infusional flavopiridol demonstrated activity in some patients with lymphomas and renal, colon gastric carcinomas. Main side effects were diarrhea and hypotension. Phase 2 trials with infusional flavopiridol, other schedules and combination with standard chemotherapies are ongoing. The second cdk modulator tested in clinical trials, UCN-01, is a PKC inhibitor that can also modulate cdk activity. Similar to flavopiridol, UCN-01 blocks cell cycle progression and promotes apoptosis. Moreover, UCN-01 may abrogate checkpoints induced by genotoxic stress due to inhibition of chk1 kinase. The first clinical trial of UCN-01 demonstrated very prolonged half-life (approximately 600 h), due to high binding affinity of UCN-01 to the human alpha-1-acid glycoprotein. Main side effects were headaches, vomiting, hypoxemia and hyperglycemia. Clinical activity was observed in some patients with melanoma and lymphoma. Trials of shorter infusions of UCN-01 or in combination with standard chemotherapeutic agents are ongoing. Although several important basic and clinical questions remain unanswered, development of cdk modulators is a reasonable strategy for cancer therapy.
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PMID:Small molecule modulators of cyclin-dependent kinases for cancer therapy. 1142 45

As a result of substantial advances in recent cancer biology, cell cycle regulation in the G1 phase has attracted a great deal of attention as a promising target for the research and treatment of cancer. Many of the important genes associated with G1 regulation have been shown to play a key role in proliferation, differentiation and oncogenic transformation and programmed cell death (apoptosis). Currently, a variety of "cytostatic" agents that affects G1 progression and/or G1/S transition are being evaluated in clinical trials. Flavopiridol is a potent inhibitor of cyclin-dependent kinases (CDKs). UCN-01 was originally found to be a PKC-selective protein kinase antagonist. More recent studies have revealed that this agent can also inhibit several CDKs and the checkpoint kinase CHK1. FR901228, MS-27-275 and SAHA are histone deacetylase inhibitors that induce changes in the transcription of specific genes via the hyperacetylation of histones. The proteasome inhibitor PS-341 disrupts the degradation process of intracellular proteins, including cell cycle regulatory proteins such as cyclins. R115777, SCH66336 and BMS-214662 are non-peptidic farnesyl transferase inhibitors that prevent p21 ras oncogene activation. Rapamycin derivative CCI-779 downregulates signals through S6 kinase and FRAP (FKBP-rapamycin associating protein), affecting the expression levels of mRNAs important for progression from G1 to S phase. 17-Allylaminogeldanamycin targets the Hsp-90 (heat shock protein-90) family of cellular chaperones regulating the function of signaling proteins. TNP-470 (AGM-1470), a fumagillin derivative shows antiangiogenic action through binding to MetAP-2 (methionine aminopeptidase-2). The antitumor sulfonamide E7070, causing a cellular accumulation in the G1 phase, has been shown to suppress the activation of CDK2 and cyclin E expression in HCT116 colorectal cancer cell line highly sensitive to the drug. With respect to several growth factor receptors such as EGFR, PDGFR, bFGFR and VEGFR, potent and specific inhibitors of receptor tyrosine kinases have been also examined as hopeful drug candidates. In this report, we review the current status of extensive efforts directed towards the discovery and development of new chemotherapeutic anticancer agents targeting cell cycle regulation in the G1 phase, with particular focus on the compounds undergoing clinical investigations.
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PMID:Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. 1156 78

Replication protein A (RPA, also known as human single-stranded DNA-binding protein) is a trimeric, multifunctional protein complex involved in DNA replication, DNA repair, and recombination. Phosphorylation of the RPA2 subunit is observed after exposure of cells to ionizing radiation (IR) and other DNA-damaging agents, which implicates the modified protein in the regulation of DNA replication after DNA damage or in DNA repair. Although ataxia telangiectasia-mutated (ATM) and DNA-dependent protein kinase (DNA-PK) phosphorylate RPA2 in vitro, their role in vivo remains uncertain, and contradictory results have been reported. Here we show that RPA2 phosphorylation is delayed in cells deficient in one of these kinases and completely abolished in wild-type, ATM, or DNA-PK-deficient cells after treatment with wortmannin at a concentration-inhibiting ATM and DNA-PK. Caffeine, an inhibitor of ATM and ATM-Rad3 related (ATR) but not DNA-PK, generates an ataxia-telangiectasia-like response in wild-type cells, prevents completely RPA2 phosphorylation in DNA-PKcs deficient cells, but has no effect on ataxia-telangiectasia cells. These observations rule out ATR and implicate both ATM and DNA-PK in RPA2 phosphorylation after exposure to IR. UCN-01, an inhibitor of protein kinase C, Chk1, and cyclin-dependent kinases, has no effect on IR-induced RPA2 phosphorylation. Because UCN-01 abrogates checkpoint responses, this observation dissociates RPA2 phosphorylation from checkpoint activation. Phosphorylated RPA has a higher affinity for nuclear structures than unphosphorylated RPA suggesting functional alterations in the protein. In an in vitro assay for DNA replication, DNA-PK is the sole kinase phosphorylating RPA2, indicating that processes not reproduced in the in vitro assay are required for RPA2 phosphorylation by ATM. Because RPA2 phosphorylation kinetics are distinct from those of the S phase checkpoint, we propose that DNA-PK and ATM cooperate to phosphorylate RPA after DNA damage to redirect the functions of the protein from DNA replication to DNA repair.
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PMID:Replication protein A2 phosphorylation after DNA damage by the coordinated action of ataxia telangiectasia-mutated and DNA-dependent protein kinase. 1173 42

Mature adult parenchymal hepatocytes can enter the S phase in the presence of growth factors such as HGF and EGF, but rarely proliferate in culture. We hypothesized that the cell cycle of hepatocytes in culture is restricted before G(2)/M phase and we attempted to identify the factor that induces cell cycle progression. We found that the conditioned medium from long-term cultured hepatocytes contained co-mitogenic activity with other growth factors, which was attributed to ethanolamine (Etn). Etn induced not only DNA synthesis but also cell replication of cultured hepatocytes with various other growth factors. Etn and HGF synergistically induced cyclin D(1), A and B expression, however, only cyclin B but not cyclin A formed a complex with Cdc2. In addition, Etn combined with HGF enhanced PKCbetaII expression and translocated PKCbetaII to the plasma membrane, and induced filopodia formation, which was inhibited by an antisense oligonucleotide against PKCbetaII. In addition, blocking the cytoskeleton rearrangement with inhibitors (colchicine, cytochalasin D, or chlerythrine (a specific PKC inhibitor)) inhibited cyclin expression and cell proliferation. Although Etn enhanced the downstream product, cellular phosphatidylethanolamine (PE), PE itself did not show any Etn-like activities on hepatocytes. Taken together, our results indicate that Etn functions as a co-replication factor to promote the cell cycle of mature hepatocytes to G(2)/M phase in the presence of growth factors. The activity is thought to be mediated by PKCbetaII-dependent cyclin B expression.
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PMID:Ethanolamine is a co-mitogenic factor for proliferation of primary hepatocytes. 1178 54

Kyowa Hakko Kogyo is developing UCN-01, a selective but non-specific inhibitor of kinases with good activity against protein kinase C (PKC) and the cyclin-dependent kinases (CDKs). This hydroxylated derivative of staurosporine has potential for the treatmentfor cancer [154087], [311028], and may be useful in the treatment of chronic lymphocytic leukemia [312089]. It is in phase I clinical trials [321641], [326004], [326256]. At the 11th NCI-EORTC-AACR Symposium (Amsterdam, November 2000), a presentation was made on UCN-01. In the initial clinical trial, in which UCN-01 was administered by continuous infusion for 72 h, a prolonged half-life of 600 h was observed. The MTD was 42.5 mg/m2/day x 3. One patient with refractory melanoma achieved a partial response, another patient with refractory anaplastic large cell lymphoma had no evaluable diseasefor more than three years [391376].
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PMID:UCN-01 Kyowa Hakko Kogyo Co. 1181 46

SSeCKS and its human orthologue, Gravin, are large scaffolding proteins that are thought to facilitate mitogenic control by anchoring key signal mediators such as protein kinase (PK) C, PKA, the plasma membrane associated isoform of alpha-1,4-galactosyltransferase (GalTase), beta2-adrenergic receptor, and cyclins. SSeCKS is also a major PKC substrate and phosphatidylserine-dependent PKC binding protein whose phosphorylation sites shares homology with a site in the MARCKS protein that encodes phosphorylation-sensitive calmodulin (CaM) binding activity. In the present study, we mapped the in vitro binding sites for CaM and cyclins on SSeCKS. Four CaM binding sites were identified by binding assays that conform to the so-called 1-5-10 motif. Notably, CaM binding was antagonized by prephosphorylation of SSeCKS by PKC. We also identified two major cyclin binding (CY) sites that overlap a major PKC phosphorylation site in SSeCKS (Ser(507/515)), and showed that cyclin D binding is attenuated if SSeCKS is prephosphorylated by PKC. These data suggest that the scaffolding activities of SSeCKS are modulated by mitogenically stimulated kinases such as PKC.
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PMID:Calmodulin and cyclin D anchoring sites on the Src-suppressed C kinase substrate, SSeCKS. 1182 Jul 72

A large body of evidence suggests that the abnormal phenotype of neoplastic astrocytes, including their excessive proliferation rate and high propensity to invade surrounding tissues, results from mutations in critical genes involved in key cellular events. These genetic alterations can affect cell-surface-associated receptors, elements of signaling pathways, or components of the cell cycle clock, conferring a gain or a loss of relevant metabolic functions of the cells. The understanding of such phenomena may allow the development of more efficacious forms of cancer treatment. Examples are therapies specifically directed against overexpressed epidermal growth factor receptor, hyperactive Ras, excessively stimulated Raf-1, overproduced ornithine decarboxylase, or aberrantly activated cyclin-dependent kinases. The applicability of some of these approaches is now being assessed in patients suffering from primary malignant central nervous system tumors that are not amenable to current therapeutic modalities. Another potentially useful therapeutic strategy against such tumors involves the inhibition of hyperactive or overexpressed protein kinase C (PKC). This strategy is justified by the decrease in cell proliferation and invasion following inhibition of the activity of this enzyme observed in preclinical glioma models. Thus, interference with PKC activity may represent a novel form of experimental cancer treatment that may simultaneously restrain the hyperproliferative state and the invasive capacity of high-grade malignant gliomas without inducing the expected toxicity of classical cytotoxic agents. Of note, the experimental use of PKC-inhibiting agents in patients with refractory high-grade malignant gliomas has indeed led to some clinical responses. The present paper reviews the current status of the biochemistry and molecular biology of PKC, as well as the possibilities for developing novel anti-PKC-based therapies for central nervous system malignancies.
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PMID:Targeting protein kinase C: new therapeutic opportunities against high-grade malignant gliomas? 1185 44

The role of Bcl-2 in photodynamic therapy (PDT) is controversial, and some photosensitizers have been shown to induce Bcl-2 degradation with loss of its protective function. Hypericin is a naturally occurring photosensitizer with promising properties for the PDT of cancer. Here we show that, in HeLa cells, photoactivated hypericin does not cause Bcl-2 degradation but induces Bcl-2 phosphorylation in a dose- and time-dependent manner. Bcl-2 phosphorylation is induced by sublethal PDT doses; increasing the photodynamic stress promptly leads to apoptosis, during which Bcl-2 is neither phosphorylated nor degraded. Bcl-2 phosphorylation involves mitochondrial Bcl-2 and correlates with the kinetics of a G(2)/M cell cycle arrest, preceding apoptosis. The co-localization of hypericin with alpha-tubulin and the aberrant mitotic spindles observed following sublethal PDT doses suggest that photodamage to the microtubule network provokes the G(2)/M phase arrest. PDT-induced Bcl-2 phosphorylation is not altered by either the overexpression or inhibition of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH(2)-terminal protein kinase 1 (JNK1) nor by inhibiting the extracellular signal-regulated kinases (ERKs) or protein kinase C. By contrast, Bcl-2 phosphorylation is selectively suppressed by the cyclin-dependent protein kinase (CDK)-inhibitor roscovitine, completely blocked by the protein synthesis inhibitor cycloheximide and enhanced by the overexpression of CDK1, suggesting a role for this pathway. However, in an in vitro kinase assay, active CDK1/cyclin B1 complex failed to phosphorylate immunoprecipitated Bcl-2, suggesting that this protein kinase may not directly modify Bcl-2. Mutation of serine-70 to alanine in Bcl-2 abolishes PDT-induced phosphorylation and restores the caspase-3 activation to the same levels of the vector-transfected cells, indicating that Bcl-2 phosphorylation may be a signal to delay apoptosis in G(2)/M phase-arrested cells.
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PMID:Phosphorylation of Bcl-2 in G2/M phase-arrested cells following photodynamic therapy with hypericin involves a CDK1-mediated signal and delays the onset of apoptosis. 1210 Nov 83

Phosphorylation of hepatitis B virus (HBV) core protein has recently been shown to be a prerequisite for pregenomic RNA encapsidation into viral capsids, but the host cell kinases mediating this essential step of the HBV replication cycle have not been identified. We detected two kinases of 95 and 115 kDa in HuH-7 total cell lysates which interacted specifically with the HBV core protein and phosphorylated its arginine-rich C-terminal domain. The 95-kDa kinase was purified and characterized as SR protein-specific kinase 1 (SRPK1) by mass spectrometry. Based on this finding, the 115-kDa kinase could be identified as the related kinase SRPK2 by immunoblot analysis. In vitro, both SRPKs phosphorylated HBV core protein on the same serine residues which are found to be phosphorylated in vivo. Moreover, the major cellular HBV core kinase activity detected in the total cell lysate showed biochemical properties identical to those of SRPK1 and SRPK2, as examined by measuring binding to a panel of chromatography media. We also clearly demonstrate that neither the cyclin-dependent kinases Cdc2 and Cdk2 nor protein kinase C, previously implicated in HBV core protein phosphorylation, can account for the HBV core protein kinase activity. We conclude that both SRPK1 and SRPK2 are most likely the cellular protein kinases mediating HBV core protein phosphorylation during viral infection and therefore represent important host cell targets for therapeutic intervention in HBV infection.
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PMID:Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein. 1213 18


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