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

The functional role of protein kinase C in the cAMP signaling cascade was investigated in human promyelocytic leukemia (HL-60) cells. Protein kinase C activation after short exposure to 100 nM phorbol 12-myristate 13-acetate (PMA) increased the intracellular cAMP level up to 3- to 5-fold after 30 min. Such enhancement was almost completely blocked by the selective protein kinase C inhibitor bisindolylmaleimide (GF 109203X). In addition, PMA, but not 4-alpha-PMA, synergistically elevated cAMP levels when adenylyl cyclase was activated directly by forskolin or indirectly by G protein activation after cholera toxin treatment or guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) treatment in digitonin-permeabilized cells. The results indicate that protein kinase C directly increases adenylyl cyclase activity and synergistically enhances it, when it is simultaneously activated otherwise. On the other hand, a 10-min treatment with PMA cut the cAMP accumulation induced by histamine, prostaglandin E2, or isoproterenol by 50-70%. However, the binding affinity and total binding of [3H]histamine to membrane receptors was not effected by PMA, suggesting that the site of protein kinase C's action is not at the receptor level. Western blot analysis of protein kinase C isozymes revealed that PMA (100 nM) caused translocation of cytosolic protein kinase C such as alpha, beta and epsilon to the particulate/membrane fraction. Treatment with a lower concentration of PMA (10 nM) translocated the protein kinase C-epsilon within 2 min, while it had little effect on the translocation of protein kinase C-alpha and -beta up to 20 min. However, simultaneous treatment with 10 nM PMA plus histamine for 5 min significantly inhibited the histamine-mediated cAMP generation, indicating that the protein kinase C-epsilon could be involved in the inhibition of receptor-mediated cAMP generation. Taken together, we conclude that PMA, through the activation of protein kinase C, has two opposite effects on the cAMP signaling cascade in HL-60 cells: a direct activation of adenylyl cyclase and an inhibition of receptor-mediated signal transduction.
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PMID:Opposing regulatory effects of protein kinase C on the cAMP cascade in human HL-60 promyelocytic leukemia cells. 972 Oct 47

Defensin transcription in HL-60 promyelocytic leukemia cells is greatly enhanced during retinoic acid (RA)-induced differentiation. We have probed this regulatory pathway by selective modulation of various kinase activities. Induction was potentiated by elevated cAMP and attenuated by protein kinase C inhibition, entirely correlated to enhanced or blocked morphological differentiation, respectively. Yet, defensin mRNA was also induced in undifferentiated HL-60 cells, but not in others, by cAMP alone. By contrast, modulators that cooperated with RA had adverse effects on the normal capacity of dimethyl sulfoxide to up regulate these transcripts as well. Thus, defensin mRNA accumulation can be selectively uncoupled from maturation stage; and transcript levels may be regulated by multiple pathways, each independently acted upon by different chemical inducers.
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PMID:Drug-activated multiple pathways of defensin mRNA regulation in HL-60 cells are defined by reversed roles of participating protein kinases. 976 52

The stress-activated protein kinase (SAPK) and mitogen-activated protein kinase (MAPK) cascades mediate cytotoxic and cytoprotective functions, respectively, in the regulation of leukemic cell survival. Involvement of these signaling systems in the cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) and modulation of ara-C lethality by protein kinase C PKC inhibition/down-regulation was examined in HL-60 promyelocytic leukemia cells. Exposure to ara-C (10 microM) for 6 hr promoted extensive apoptotic DNA damage and cell death, as well as activation of PKC. This response was accompanied by downstream activation of the SAPK and MAPK cascades. PKC-dependent MAPK activity seemed to limit ara-C action in that the toxicity of ara-C was enhanced by pharmacological reductions of PKC, MAPK, or both. Thus, ara-C action was (1) partially attenuated by diradylglycerols, which stimulated PKC and MAPK, but (2) dramatically amplified by sphingoid bases, which inhibited PKC and MAPK. The cytotoxicity of ara-C also was substantially increased by pharmacological reductions of PKC, including down-regulation of PKC by chronic preexposure to the macrocyclic lactone bryostatin 1 or inhibition of PKC by acute coexposure to the dihydrosphingosine analog safingol. Significantly, both of these manipulations prevented activation of MAPK by ara-C. Moreover, acute disruption of the MAPK module by AMF, a selective inhibitor of MEK1, suppressed both basal and drug-stimulated MAPK activity and sharply increased the cytotoxicity of ara-C, suggesting the direct involvement of MAPK as a downstream antiapoptotic effector for PKC. None of these chemopotentiating agents enhanced ara-CTP formation. Ceramide-driven SAPK activity did not seem to mediate drug-induced apoptosis, given that (1) neutralization of endogenous tumor necrosis factor-alpha with monoclonal antibodies or soluble tumor necrosis factor receptor substantially reduced ceramide generation and SAPK activation by ara-C, whereas the induction of apoptosis was unaffected; (2) pharmacological inhibition of sphingomyelinase by 3-O-methoxysphingomyelin reduced ceramide generation and SAPK activation without limiting the drug's cytotoxicity; and (3) potentiation of ara-C action by bryostatin 1 or safingol was not associated with further stimulation of SAPK. These observations collectively suggest a primary role for decreased MAPK, rather than increased SAPK, in the potentiation of ara-C cytotoxicity by interference with PKC-dependent signaling.
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PMID:Evidence for involvement of mitogen-activated protein kinase, rather than stress-activated protein kinase, in potentiation of 1-beta-D-arabinofuranosylcytosine-induced apoptosis by interruption of protein kinase C signaling. 980 19

1,25-dihydroxyvitamin D3 (calcitriol) is not only an antirachitic agent, but also a well known regulator of cell differentiation. HL-60 promyelocytic leukemia cells differentiate to monocytes upon treatment with calcitriol. We describe here, that PI3-K inhibitors are able to block the differentiation induced by calcitriol in HL-60 cells. Also the downstream effector of PI3-K, p70S6K ribosomal protein kinase seems to be involved in HL-60 cell differentiation. PKC alpha and PKC delta are activated and translocated to the nucleus upon exposure of cells to calcitriol. However in our experiments the inhibition of PKC did not result in an inhibition of calcitriol induced differentiation of HL-60 cells. On the contrary, the use of thapsigargin, caused the differentiation process to stop.
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PMID:Evidence that phosphatidylinositol 3-kinase and p70S6K protein are involved in differentiation of HL-60 cells induced by calcitriol. 985 32

A spiroiridal-type triterpenoid, 28-deacetylbelamcandal (1), was isolated from the rhizomes of Iris tectorum as an active principle that stimulated differentiation of human promyelocytic leukemia (HL-60) cells, a short-term screening method for 12-O-tetradecanoylphorbol 13-acetate (TPA)-type tumor promoters. In the same manner as TPA, compound 1 bound to protein kinase C (PKC) and activated PKC, and induced tumor necrosis factor-alpha release from HL-60 cells. In an in vivo study, groups treated with 100 microg 7, 12-dimethylbenz[a]anthracene plus 400 nmol of 1 showed 64.3% tumor incidence by week 20. It has thus been demonstrated that 1 represents a new structural class of mouse skin-tumor promoters.
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PMID:28-deacetylbelamcandal, a tumor-promoting triterpenoid from Iris tectorum. 1007 62

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) suppresses c-myc expression during differentiation of HL-60 cells along the monocytic pathway by blocking transcriptional elongation at the first exon/intron border of the c-myc gene. In the present study, the physiological relevance of three putative regulatory protein binding sites found within a 280-base pair region in intron 1 of the c-myc gene was explored. HL-60 promyelocytic leukemia cells were transiently transfected with three different c-myc promoter constructs cloned upstream of a chloramphenicol acetyltransferase (CAT) reporter gene. With the wild-type c-myc promoter construct (pMPCAT), which contains MIE1, MIE2, and MIE3 binding sites, 1,25-(OH)2D3 was able to decrease CAT activity by 45.4 +/- 7.9% (mean +/- S.E., n = 8). The ability of 1, 25-(OH)2D3 to inhibit CAT activity was significantly decreased to 18. 5 +/- 4.3% (59.3% reversal, p < 0.02) when examined with a MIE1 deletion construct (pMPCAT-MIE1). Moreover, 1,25-(OH)2D3 was completely ineffective at suppressing CAT activity in cells transfected with pMPCAT-287, a construct without MIE1, MIE2, and MIE3 binding sites (-6.5 +/- 10.9%, p < 0.002). MIE1- and MIE2-binding proteins induced by 1,25-(OH)2D3 had similar gel shift mobilities, while MIE3-binding proteins migrated differently. Furthermore, chelerythrine chloride, a selective protein kinase C (PKC) inhibitor, and a PKCbeta antisense oligonucleotide completely blocked the binding of nuclear proteins induced by 1,25-(OH)2D3 to MIE1, MIE2, and MIE3. A 1,25-(OH)2D3-inducible MIE1-binding protein was identified to be HOXB4. HOXB4 levels were significantly increased in response to 1,25-(OH)2D3. Taken together, these results indicate that HOXB4 is one of the nuclear phosphoproteins involved in c-myc transcription elongation block during HL-60 cell differentiation by 1,25-(OH)2D3.
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PMID:c-myc intron element-binding proteins are required for 1, 25-dihydroxyvitamin D3 regulation of c-myc during HL-60 cell differentiation and the involvement of HOXB4. 1008 75

The antitumoral activity of non-steroidal antiestrogens on promyelocytic leukemia HL60 and T lymphoblastic MOLT3 cell lines was studied. Tamoxifen and its derivatives, clomiphene and nafoxidine, caused reduction of cell viability in a dose-dependent manner. These drugs showed differences in their potency following four days incubation, with nafoxidine being the most efficient inhibitor and tamoxifen the least active. Apoptosis was induced as assessed by the DNA ladder pattern and formation of pre G0/G1 population as detected by flow cytometry analysis of DNA. The effect of these drugs was abrogated by antioxidants: alpha-tocopherol was most effective in antagonizing the drugs' effect. N-acetyl L-cysteine reversed mainly the decrease in cell viability caused by the drugs, but was less active on induction of apoptosis. GF109203X, a protein kinase inhibitor, attenuated apoptosis induced by clomiphene in MOLT3 cells. The results suggest that the antileukemic activity of the antiestrogens is mediated by oxidative stress and protein kinase C (PKC) activation. Triphenylethylene antiestrogens and their derivatives may be used as antileukemic drugs which kill cells by apoptosis mediated by oxidative stress and activation of PKC.
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PMID:Non-steroidal antiestrogens induce apoptosis in HL60 and MOLT3 leukemic cells; involvement of reactive oxygen radicals and protein kinase C. 1047 Jan 53

The effects of phorbol 12-myristate 13-acetate (PMA) on DNA damage-induced apoptosis were examined in promyelocytic leukemia cells, U937, in comparison with other differentiation-inducing agents to clarify the role of protein kinase C (PKC) vis-a-vis cellular differentiation in apoptosis. The apoptosis of U937 cells was observed at as early as 1-1.5 h following UV irradiation, with most cells being in apoptotic state at 3 h. Pretreatment with PMA for as short as 5 min was sufficient to inhibit apoptosis induced by UV irradiation, whereas apparent changes in cell cycle distributions and expression of differentiation markers by PMA were not observed until 12 h and 48 h, respectively. The inhibition of apoptosis by PMA was completely abolished by the pretreatment with calphostin C, a PKC inhibitor, and 4 alpha-phorbor 12,13-didecanoate, which is unable to activate PKC, did not protect U937 cells against apoptosis induced by UV irradiation. Other differentiation inducers, such as cyclic AMP and active vitamin D3, did not affect the UV-induced apoptosis of U937 cells. Taken together, it was suggested that PMA inhibits DNA damage-induced apoptosis through the activation of PKC rather than as a result of differentiation of U937 cells.
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PMID:Phorbol ester inhibits DNA damage-induced apoptosis in U937 cells through activation of protein kinase C. 1057 97

In human promyelocytic leukemia cell line HL60, apoptosis was induced by treatment with gossypol that is an inhibitor of protein kinase C. Gossypol acetic acid was added to HL 60 cells at 50, 100, 150 and 200 microM concentrations for six hours. Morphological features of apoptosis as well as internucleosomal DNA fragmentation were evaluated by light microscope, agarose gel electrophoresis and spectrofluorometric quantitation. Our results indicated that with the effective concentrations of gossypol (50 and 100 microM), apoptosis was induced in HL 60 cells.
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PMID:Gossypol induced apoptosis in the human promyelocytic leukemia cell line HL 60. 1062 8

The ability of the promyelocytic leukemia HL60 cell line to differentiate in response to various stimuli has provided a widely used model of differentiation. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), acting via its cellular receptor protein kinase C(PKC), induces these cells to acquire a monocytic phenotype. We set out to identify the specific isoform of the multigene PKC family that is involved in this differentiation event. To do so, we utilized a highly specific PKCbeta inhibitor, LY379196. We found that LY379196 could prevent the growth arrest, cellular adherence, and changes in several marker proteins that occur after the addition of TPA to HL60 cells and that these effects were not simply due to nonspecific cytotoxicity. Thus, the present studies provide strong evidence that the beta isoform of PKC plays a critical role in TPA-induced HL60 monocytic differentiation.
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PMID:The protein kinase C beta-specific inhibitor LY379196 blocks TPA-induced monocytic differentiation of HL60 cells the protein kinase C beta-specific inhibitor LY379196 blocks TPA-induced monocytic differentiation of HL60 cells. 1070 78


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