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)

The BCL2 (B cell lymphoma/leukemia-2) proto-oncogene encodes a 26-kDa protein that has been localized to the inner mitochondrial membrane and that has been shown to enhance the survival of some types of hematopoietic cells. Here we show that NIH3T3 fibroblasts stably transfected with a BCL2 expression plasmid exhibit reduced dependence on competence-inducing growth factors (platelet-derived growth factor, PDGF; epidermal growth factor, EGF) for initiation of DNA synthesis. The importance of BCL2 for growth factor-induced proliferation of these cells was further confirmed by the useage of BCL2 antisense oligodeoxynucleotides. The mechanisms by which overexpression of p26 BCL2 contributes to fibroblast proliferation are unknown, but do not involve alterations in: (a) the production of inositol triphosphates (IP3), (b) PDGF-induced transient elevations in cytosolic Ca2+ ions, or (c) the activity of protein kinase C enzymes in these transfected cells. The results imply that changes in mitochondrial functions play an important role in the early stages of the cell cycle that render 3T3 cells competent to respond to the serum progression factors that stimulate entry into S-phase.
 ...
PMID:Mitochondrial protein p26 BCL2 reduces growth factor requirements of NIH3T3 fibroblasts. 207 Aug 13

Epidermal Growth Factor (EGF) and Tetradecanoyl Phorbol Acetate (TPA) initiate signalling cascades in C3H 10T1/2 fibroblasts by primarily activating distinct protein kinases, the EGF receptor tyrosine kinase and protein kinase C respectively; there is no signal crossover at the initiation of signalling. Nevertheless, we show here that both agents rapidly elicit common intracellular responses, including the phosphorylation of complexed and chromatin-associated forms of a 33 kDa phosphoprotein (pp33), that of a 15 kDa chromatin-associated phosphoprotein (pp15), as well as the transcriptional activation of a common subset of genes including the c-fos proto-oncogene. 2-aminopurine specifically abolishes complexed and chromatin-associated pp33 phosphorylation in response to EGF and TPA, as well as the induction of c-fos by both agents. The activation of protein kinase C and the levels of transcription factors that bind to the serum response element (SRE), TPA response element (TRE) or NFkB sites in stimulated cells are relatively unaffected by 2-aminopurine. This, to our knowledge, is the first demonstration that it is possible, by using 2-aminopurine which selectively blocks TPA-stimulated pp33 phosphorylation, to block c-fos induction in TPA-treated cells although protein kinase C remains fully active. Further, we show here that although EGF- and TPA-stimulated induction of c-fos is abolished by 2-aminopurine, the appearance of TRE-binding activity in nuclear extracts of stimulated cells is unaffected, suggesting that EGF- and TPA-stimulated induction of TRE-binding activity utilises existing proteins and is not dependent on fresh c-FOS synthesis. These results imply that 2-aminopurine-sensitive complexed and chromatin-associated pp33 phosphorylation may be crucial to c-fos induction in response to EGF and TPA.
 ...
PMID:2-Aminopurine abolishes EGF- and TPA-stimulated pp33 phosphorylation and c-fos induction without affecting the activation of protein kinase C. 210 92

The product of the jun proto-oncogene has been identified as one form of the transcription factor AP-1. The p55fos protein associates with jun/AP-1 by means of a heterodimer which requires intact 'leucine zipper' domains of both proteins. The fos/jun heterodimer binds to and activates transcription from TPA-responsive promoter elements (TGACTCA), which represent one final target of the protein kinase C pathway. The other main signal transduction pathway, initiated by the activation of the adenylate cyclase, involves the transcription factor CREB. The promoter element recognized by CREB, a cyclic AMP responsive element (CRE), consist of a palyndromic sequence similar to a TRE (TGACGTCA). We show that jun efficiently trans-activates CRE sequences and that fos and jun efficiently bind and cooperate in activating CRE promoter elements. The similarity between TRE and CRE sequences may involve an interplay in transcriptional regulation and 'cross-talk' between components of the two major signal transduction pathways.
 ...
PMID:Cross-talk in signal transduction: TPA-inducible factor jun/AP-1 activates cAMP-responsive enhancer elements. 210 94

We describe in vitro studies undertaken to characterize the expression of the proto-oncogene c-jun during differentiation of B-CLL cells. The phorbol ester TPA and the natural compound Bryostatin 1 (Bryo) were used to directly stimulate protein kinase C (PKC) while the calcium ionophone A23187 was employed to increase intracellular Ca2+. In quiescent cells c-jun mRNA expression was undetectable or at low levels. Upon treatment with TPA or Bryo, the steady-state levels of c-jun mRNA increased rapidly, reached a maximum at 0.5 or 1 hr, and then decreased in the B-CLL cells from all five patients analyzed; this reaction was augmented by the addition of A23187. Induction of c-jun mRNA by direct stimulation of PKC could be blocked by the PKC inhibitor H7. The present observations, along with other results on the induction of long-term phenotypical cellular changes, such as alteration of morphology and other features of differentiation, support the notion that the second messenger (via PKC) and the third messenger (via proto-oncogene products) pathways are intact in B-chronic lymphocytic leukemia cells.
 ...
PMID:Expression of proto-oncogene c-jun during differentiation of B-chronic lymphocytic leukemia. 211 1

The proto-oncogene c-fos has been implicated in the modulation of various cell functions. We have found that thrombin, a pleiotropic activator of endothelial cells, induced c-fos mRNA in human umbilical vein endothelial cells (HEC). This effect was dose-related (0.05 to 1.0 U/mL) and transient (maximal after 1 hour and negligible within 4 hours). Since thrombin activates phosphoinositide (PI) turnover through a pertussis toxin (PT)-sensitive guanosine triphosphate-binding regulatory protein(s) (G-protein) with subsequent stimulation of protein kinase C (PKC) and Ca2+ movements, we investigated whether these intracellular pathways are also responsible for c-fos induction. PT inhibited thrombin's effect on c-fos expression, but had no effect on c-fos expression by phorbol myristate acetate (PMA). Down regulation of PKC by prolonged exposure to PMA had no effect on thrombin and ionomycin stimulation of c-fos, but inhibited PMA activation of this gene. Quenching of the Ca1(2+) increase in response to quin2 loading in the absence of external Ca2+ suppressed thrombin activity on c-fos transcription. Under the same conditions PMA activity was not inhibited or only partially inhibited. Interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (bFGF) stimulation of c-fos mRNA level were not inhibited by quin2; on the contrary, ionomycin effect was blocked by this agent. These results indicate that thrombin-induced c-fos expression in HEC does not require a fully active PKC but is dependent on normal intracellular Ca2+ availability.
 ...
PMID:Thrombin induces c-fos expression in cultured human endothelial cells by a Ca2(+)-dependent mechanism. 211 37

Both increases in c-fos proto-oncogene expression and intracellular free calcium ([Ca2+]i) have been implicated as necessary components of the signal transduction pathway by which platelet-derived growth factor (PDGF) stimulates DNA synthesis in cultured BALB/c3T3 fibroblasts. To determine the interrelationship between PDGF-induced increases in c-fos proto-oncogene expression and [Ca2+]i, purified, recombinant BB and AA homodimeric isoforms of PDGF were used to evaluate the dose-response relationships and mechanisms of growth factor-induced changes in these two parameters as well as DNA synthesis. Concentration-dependent increases in [Ca2+]i, c-fos expression, and [3H]thymidine incorporation were observed with both BB and AA PDGF isoforms. BB PDGF was consistently more potent and efficacious than the AA isoform in eliciting a given response. The [Ca2+]i dependency of PDGF-induced increases in c-fos expression and DNA synthesis was determined by pretreatment of cells with agents that inhibit increases in [Ca2+]i: BAPTA, Quin-2, and TMB-8. Under these conditions, PDGF-induced DNA synthesis was blocked, whereas c-fos expression was enhanced. Conversely, in cells made deficient in protein kinase C (PKC) activity by prolonged treatment with phorbol ester, BB and AA PDGF-induced c-fos expression was inhibited by 75-80%, while PDGF-induced increases in [Ca2+]i and DNA synthesis were unaffected or enhanced. Additionally, the PKC-independent component of PDGF-stimulated c-fos expression was found to be independent of increases in [Ca2+]i. These data suggest that 1) both BB and AA PDGF isoforms elicit alterations in [Ca2+]i and c-fos proto-oncogene expression through the same or similar mechanisms in BALB/c3T3 fibroblasts, 2) PDGF-stimulated increases in [Ca2+]i are not required for c-fos expression, and 3) distinct pathways regulate PDGF-induced c-fos expression and mitogenesis, with c-fos expression being substantially PKC-dependent yet [Ca2+]i-independent, while mitogenesis is [Ca2+]i-dependent yet PKC-independent.
 ...
PMID:Interrelationships of platelet-derived growth factor isoform-induced changes in c-fos expression, intracellular free calcium, and mitogenesis. 213 98

THP-1 is a factor-indepencent, monocytic leukemia cell line which differentiates into adherent macrophages upon treatment with 12-O-tetra-decanoylphorbol-13-acetate (TPA). Unlike its normal counterparts, THP-1 cells display only minimal levels of proto-oncogene c-FMS RNA which encode for membrane M-CSF receptors. Northern blot analysis showed that the c-FMS mRNA levels in THP-1 cells was greatly enhanced during TPA-induced monocytic differentiation. Despite the acquisition of functional activities and induction of c-FMS transcripts after TPA treatment, no surface M-CSF receptors were detected on the THP-1 cells. The inducing activity associated with TPA was completely abrogated when THP-1 cells were pretreated with staurosporine, a potent protein kinase C (PK-C) inhibitor. It is concluded that the activation of the PK-C system is a part of the metabolic cascade essential for the initiation of monocytic differentiation in THP-1 cells.
 ...
PMID:Inhibition of TPA-induced monocytic differentiation in THP-1 human monocytic leukemic cells by staurosporine, a potent protein kinase C inhibitor. 214 May 92

Cells of the Y-1 corticoadrenal line are: (a) functional, (b) cell cycle-arrested by adrenocorticotropic hormone (ACTH), (c) tumorigenic, and (d) c-Ki-ras overexpressing. We here report that the phorbol ester phorbol 12-myristate 13-acetate (PMA) mimics all ACTH-specific effects in Y-1 cells, namely: (a) steroid-ogenesis stimulation, (b) cell cycle block, and (c) cell shape change. In addition, both ACTH and PMA caused a rapid and transient induction of the c-fos proto-oncogene while having no effect on c-Ki-ras mRNA steady state levels. Dibutyryl cAMP, known to elicit ACTH effects in Y-1 cells, was a poor inducer of the c-fos gene. PMA pretreatment rendered Y-1 cells unresponsive to ACTH. These results suggest that protein kinase C is likely to be involved in the mechanisms of action of ACTH.
 ...
PMID:Phorbol ester mimics ACTH action in corticoadrenal cells stimulating steroidogenesis, blocking cell cycle, changing cell shape, and inducing c-fos proto-oncogene expression. 215 81

Colony-stimulating factor-1 (CSF-1 or M-CSF) regulates pleiotropic developmental and functional responses of macrophages and their committed bone marrow progenitors and supports the viability of cells of the mononuclear phagocyte lineage. Its actions are mediated through its binding to cell surface CSF-1 receptors (CSF-1R) that exhibit ligand-stimulated tyrosine kinase activity. CSF-1R-induced phosphorylation of intracellular protein substrates initiates a cascade of biochemical reactions that relay signals to the cell nucleus, elicit transcription of CSF-1-responsive genes and culminate in cell division. The actions of the CSF-1R kinase can be interrupted by binding of certain monoclonal antibodies to the extracellular domain of the receptor or by agents which activate protein kinase C and accelerate receptor turnover. CSF-1R is encoded by the c-fms proto-oncogene, and specific genetic alterations, which constitutively activate the receptor kinase, provide sustained signals for cell growth leading to cell transformation. Perturbations in the structure or expression of the c-fms proto-oncogene might therefore contribute to leukemia.
 ...
PMID:Regulation of mononuclear phagocyte proliferation by colony-stimulating factor-1. 215 78

Tumor-associated macrophages (TAM) have peculiar membrane phenotype and functional properties. In an effort to unravel possible molecular determinants associated with the reprogramming of mononuclear phagocytes that infiltrate tumors, we have investigated the expression of immediate-early genes in TAM from murine sarcomas. c-fos is a prototypic immediate oncogene, with transregulatory function on gene transcription, expressed by myelomonocytic cells and induced by certain activation signals. TAM from three murine sarcomas expressed basal levels of c-fos transcripts considerably higher than those of peritoneal exudate macrophages (PEM). Activation of myelomonocytic cells by bacterial LPS is associated with an early transient increase in c-fos transcription. Unlike PEM, TAM did not show any increase in c-fos expression after exposure to LPS. A similar unresponsiveness to LPS stimulation was observed in macrophages isolated from peritoneal ascitic tumors. c-fos expression in macrophages can be induced via protein kinase C activation or via an increase in cAMP levels. Unlike PEM, TAM did not respond to the protein kinase C activator PMA and to cholera toxin. After culture for 18 to 20 h, c-fos expression in TAM declined, and concomitantly, TAM completely recovered responsiveness to LPS in terms of augmented oncogene mRNA levels. These results demonstrate that TAM from murine sarcomas have an altered expression of the c-fos proto-oncogene, with high basal levels and unresponsiveness to augmenting signals, reversible upon in vitro culture. The altered c-fos expression in TAM may reflect exposure to cytokines present in the tumor microenvironment and may underlie at least some of the peculiar properties of TAM.
 ...
PMID:Expression of c-fos proto-oncogene in tumor-associated macrophages. 216 81


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