Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapamycin and its derivatives are promising anticancer agents, but the exact mechanisms by which these drugs induce cell cycle arrest and inhibit tumor growth are unknown. A biochemical analysis of human mammary tumor cell lines indicated that rapamycin-induced antiproliferative effects correlated with down-regulation of cellular p21 levels and the levels of p21 in cyclin-dependent kinase (Cdk) 2 and 4 complexes. Cyclin D1 overexpression reversed rapamycin action and this reversal correlated with increased levels of cellular p21, higher levels of p21 associated with Cdk2, and stabilization of cyclin D1/Cdk2/p21/proliferating cell nuclear antigen (PCNA) complexes. Experiments using a novel cyclin D1-Cdk2 fusion protein or a kinase-dead mutant of the fusion protein indicated that reversal of rapamycin action required not only the formation of complexes with p21 and PCNA but also complex-associated kinase activity. Similar results were observed in vivo. The rapamycin derivative RAD001 (everolimus) inhibited the growth of mouse mammary tumors, which correlated with the disruption of cyclin D1/Cdk2 complexes. The potential implications of these results with respect to the use of rapamycin derivatives in breast cancer therapy are discussed.
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PMID:Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes. 1642 43

Aberrant activity of hypothalamic-pituitary-adrenal (HPA) axis is often observed in psychiatric disorders and both antidepressant and antipsychotic drugs are known to ameliorate some deleterious effects of glucocorticoids on brain function. Some neurosteroids possess antidepressant and neuroleptic-like properties and attenuate the stress-activated HPA axis activity. However, intracellular mechanism of neurosteroid interaction with glucocorticoids has not been elucidated. We evaluated effects of some neurosteroids on functional activity of glucocorticoid receptor (GR) in vitro. A combined treatment with antipsychotic drugs and involvement of some protein kinases in allopregnanolone effect on GR function were also studied. The effects of allopregnanolone, its two isomers (5beta-pregnan-3alpha-ol-20-one and 5alpha-pregnan-3beta-ol-20-one) and dehydroepiandrosterone sulfate (DHEAS) on the corticosterone-induced chloramphenicol acetyl transferase (CAT) activity were evaluated in mouse fibroblast cells stably transfected with mouse mammary tumor virus (MMTV)-CAT plasmid. We found that allopregnanolone (1-100 microM) and, to a lesser extent, both its isomers inhibited the GR-mediated gene transcription in a concentration-dependent manner. In contrast, DHEAS at the concentration up to 100 microM was inactive. Further experiments revealed that allopregnanolone and antipsychotic drugs (chlorpromazine and clozapine) showed a moderate, additive inhibitory effect on the GR function. With respect to intracellular mechanism of allopregnanolone action, we showed that this neurosteroid inhibited protein kinase C (PKC) activity, decreased the level of PKCalpha isoenzyme in the membrane fraction and decreased the amount of active phosphorylated form of extracellular signal-regulated kinase-mitogen-activated protein kinase (ERK-MAPK) in LMCAT cells. Since PKC and ERK-MAPK inhibitors attenuate the corticosterone-mediated gene transcription, the above findings suggest that allopregnanolone effect on GR function involves interaction with these kinase pathways. On the other hand, allopregnanolone had no effect on protein kinase A (PKA) activity. These data indicate that pregnanolone derivatives, like antidepressants and antipsychotic drugs, may attenuate some glucocorticoid effects via inhibition of GR-mediated gene transcription. Furthermore, the inhibitory effect of allopregnanolone on the corticosterone-induced gene transcription in LMCAT cells depended on the inhibition of PKC and ERK-MAPK pathways.
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PMID:Effects of neurosteroids on glucocorticoid receptor-mediated gene transcription in LMCAT cells--a possible interaction with psychotropic drugs. 1658 Dec 32

The membrane mucin Muc4 has been shown to alter cellular behavior through both anti-adhesive effects on cell-cell and cell-extracellular matrix interactions and its ability to act as an intramembrane ligand for the receptor tyrosine kinase ErbB2. The ERK pathway is regulated by both cell-matrix and cell-cell adhesion. An analysis of the effects of Muc4 expression on ERK phosphorylation in mammary tumor and epithelial cells, which exhibit both adhesion-dependent growth and contact inhibition of growth, showed that the effects are density dependent, with opposing effects on proliferating cells and contact-inhibited cells. In these cells, cell-matrix interactions through integrins are required for activation of the ERK mitogenesis pathway. However, cell-cell interactions via cadherins inhibit the ERK pathway. Expression of Muc4 reverses both of these effects. In contact-inhibited cells, Muc4 appears to activate the ERK pathway at the level of Raf-1; this activation does not depend on Ras activation. The increase in ERK activity correlates with an increase in cyclin D(1) expression in these cells. This abrogation of contact inhibition is dependent on the number of mucin repeats in the mucin subunit of Muc4, indicative of an anti-adhesive effect. The mechanism by which Muc4 disrupts contact inhibition involves a Muc4-induced relocalization of E-cadherin from adherens junctions at the lateral membrane of the cells to the apical membrane. Muc4-induced abrogation of contact inhibition may be an important mechanism by which tumors progress from an early, more benign state to invasiveness.
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PMID:Membrane mucin Muc4 induces density-dependent changes in ERK activation in mammary epithelial and tumor cells: role in reversal of contact inhibition. 1689 13

Expression of the cyclin-dependent kinase (Cdk) inhibitor (p27(Kip1)) is frequently reduced in human tumors, often correlating with poor prognosis. p27(Kip1) functions as a haploinsufficient tumor suppressor; however, the mechanism by which one allele of p27(Kip1) regulates oncogenic signaling in vivo is not well understood. We therefore investigated the mechanisms by which p27(Kip1) inhibits mammary tumor onset. Using the common background strain of FVB, p27(Kip1) heterozygosity (p27(+/-)) accelerated ErbB2-induced mammary tumorigenesis. We conducted microarray analyses of mammary tumors developing in mice with genetic haploinsufficiency for p27(Kip1) expressing a mammary-targeted ErbB2 oncogene. Global gene expression profiling and Western blot analysis of ErbB2/p27(+/-) tumors showed that the loss of p27(Kip1) induced genes promoting lymphangiogenesis, cellular proliferation, and collaborative oncogenic signaling (Wnt/beta-catenin/Tcf, Cdc25a, Smad7, and Skp2). Skp2 expression was induced by ErbB2 and repressed by p27(Kip1). Degradation of p27(Kip1) involves an SCF-type E3 ubiquitin ligase, including Skp2. The Skp2 component of the SCF(SKP2) complex that degrades p27(Kip1) was increased in ErbB2 tumors correlating with earlier tumor onset. In both murine and human ErbB2-overexpressing breast cancers, p27(Kip1) levels correlated inversely with Skp2. p27(Kip1) haploinsufficiency activated Wnt/beta-catenin/hedgehog signaling. Reintroduction of p27(Kip1) inhibited beta-catenin induction of Tcf-responsive genes (Siamosis, c-Myc, and Smad7). p27(Kip1) is haploinsufficient for ErbB2 mammary tumor suppression in vivo and functions to repress collaborative oncogenic signals including Skp2 and Wnt/beta-catenin signaling.
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PMID:p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling. 1695 Nov 65

Previously, we showed that the bioactive green tea polyphenol epigallocatechin-3-gallate (EGCG) inhibits growth in soft agar of breast cancer cells with Her-2/neu overexpression. Using gene expression profiling, here we show that EGCG treatment of Her-2/neu-driven mammary tumor cells alters the expression of key regulators in the epithelial to mesenchymal transition (EMT) pathway, reducing invasive phenotype. Specifically, the epithelial genes E-cadherin, gamma-catenin, MTA3, and estrogen receptor alpha (ERalpha) were up-regulated by EGCG, whereas the proinvasive snail gene was down-regulated. Consistently, EGCG inhibited branching colony growth and invasion in Matrigel. EGCG treatment similarly inhibited invasive phenotype of mouse mammary tumor cells driven by Nuclear Factor-kappaB c-Rel and protein kinase CK2, frequently found overexpressed in human breast disease. Recently, we identified the Forkhead box O transcription factor FOXO3a as a major transcriptional regulator of ERalpha. Given the pivotal role of ERalpha in preventing EMT, we hypothesized that the activation of FOXO3a by EGCG plays an important role in the observed reversal of invasive phenotype in ERalpha-positive breast cancer cells. EGCG treatment activated FOXO3a. Ectopic expression of a constitutively active FOXO3a overrode transforming growth factor-beta1-mediated invasive phenotype and induced a more epithelial phenotype, which was dependent on ERalpha expression and signaling. Conversely, a dominant negative FOXO3a reduced epithelial phenotype of ERalpha-low breast cancer cells. These results identify, for the first time, a role for FOXO3a in the inhibition of invasive phenotype in breast cancer cells with active ERalpha signaling and elucidate a novel mechanism whereby EGCG represses EMT of breast cancer cells.
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PMID:Activation of FOXO3a by the green tea polyphenol epigallocatechin-3-gallate induces estrogen receptor alpha expression reversing invasive phenotype of breast cancer cells. 1757 43

In Con8 rat mammary epithelial tumor cells, indirect immunofluorescence revealed that Sgk (serum- and glucocorticoid-regulated kinase) and Erk/MAPK (extracellular signal-regulated protein kinase/mitogen activated protein kinase) co-localized to the nucleus in serum-treated cells and to the cytoplasmic compartment in cells treated with the synthetic glucocorticoid dexamethasone. Moreover, the subcellular distribution of the importin-alpha nuclear transport protein was similarly regulated in a signal-dependent manner. In vitro GST-pull down assays revealed the direct interaction of importin-alpha with either Sgk or Erk/MAPK, while RNA interference knockdown of importin-alpha expression disrupted the localization of both Sgk and Erk into the nucleus of serum-treated cells. Wild type or kinase dead forms of Sgk co-immunoprecipitated with Erk/MAPK from either serum- or dexamethasone-treated mammary tumor cells, suggesting the existence of a protein complex containing both kinases. In serum-treated cells, nucleus residing Sgk and Erk/MAPK were both hyperphosphorylated, indicative of their active states, whereas, in dexamethasone-treated cells Erk/MAPK, but not Sgk, was in its inactive hypophosphorylated state. Treatment with a MEK inhibitor, which inactivates Erk/MAPK, caused the relocalization of both Sgk and ERK to the cytoplasm. We therefore propose that the signal-dependent co-localization of Sgk and Erk/MAPK mediated by importin-alpha represents a new pathway of signal integration between steroid and serum/growth factor-regulated pathways.
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PMID:The stimulus-dependent co-localization of serum- and glucocorticoid-regulated protein kinase (Sgk) and Erk/MAPK in mammary tumor cells involves the mutual interaction with the importin-alpha nuclear import protein. 1769 13

Exposure to and bioaccumulation of lipophilic environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs), has been implicated in breast cancer. Treatment of female rats with the prototypic xenobiotic PAH 7,12-dimethylbenz(a)anthracene (DMBA) induces mammary tumors with an invasive phenotype. Here, we show that green tea prevents or reverses loss of the epithelial marker E-cadherin on the surface of DMBA-induced in situ cancers. To investigate the mechanism(s) leading to a less invasive phenotype, the effects of the green tea polyphenol epigallocatechin-3 gallate (EGCG) on mammary tumor cells were assessed. EGCG reversed epithelial to mesenchymal transition (EMT) in DMBA-treated NF-kappaB c-Rel-driven mammary tumor cells and reduced levels of c-Rel and the protein kinase CK2. Ectopic coexpression of c-Rel and CK2alpha in untransformed mammary epithelial cells was sufficient to induce a mesenchymal gene profile. Mammary tumors and cell lines derived from MMTV-c-Rel x CK2alpha bitransgenic mice displayed a highly invasive phenotype. Coexpression of c-Rel and CK2, or DMBA exposure induced the aryl hydrocarbon receptor (AhR) and putative target gene product Slug, an EMT master regulator, which could be reversed by EGCG treatment. Thus, activation of c-Rel and CK2 and downstream targets AhR and Slug by DMBA induces EMT; EGCG can inhibit this signaling.
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PMID:Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. 1808 4

The aim of the present study was to investigate effects of some classical and new antidepressants on functional activity of the glucocorticoid receceptor (GR) induced by low corticosterone concentration in mouse fibroblast cells stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase plasmid (LMCAT cells). We found that the transcriptional activity of GR stimulated by 50 nM corticosterone was strongly attenuated by imipramine, desipramine, fluoxetine and tianeptine in a concentration-dependent way, whereas reboxetine had only a weak effect and venlafaxine was inactive. Further study revealed that the inhibitor of c-Jun N-terminal kinase - mitogen-activated protein kinase (JNK-MAPK), SP600125 (0.1 microM), reversed the imipramine-induced suppression of GR function, whereas the inhibitor of extracellular signal-regulated kinase (ERK)-MAPK, PD 98059 (15 microM), potentiated the antidepressant action. No effect of selective inhibitors of p38-MAPK, phosphatidylinositol 3-kinase (PI3-K)/Akt, and glycogen synthase kinase (GSK-3) on the imipramine-induced inhibition of GR function was detected. These data indicate that the functional activity of GR evoked by low corticosterone concentration in LMCAT cells is efficiently inhibited by tricyclic antidepressants. Moreover, it was found that JNK- and ERK-MAPK were oppositely involved in the regulation of the imipramine-induced inhibition of the GR functional activity. Thus, the present study supports the notion that the interaction of antidepressants with GR may play a role in attenuating pathological hyperactivity of HPA axis in depression.
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PMID:Effect of some antidepressants on the low corticosterone concentration-induced gene transcription in LMCAT fibroblast cells. 1844 95

Mammary cancer is among the most frequently observed canine tumors in unspayed female dogs resulting in death due to metastatic disease. These tumors are excellent models of human breast cancer but until recently there was only anecdotal evidence regarding underlying genetic defects. We recently reported expression defects in the cyclin-dependent kinase p21/Cip1 and p53 among three independent canine mammary tumor (CMT) cell lines derived from spontaneous canine mammary cancers. We investigated further defects in the same three cell lines focusing on additional tumor suppressor gene defects in cyclin-dependent kinase inhibitors. p27/KIP1 appeared normally expressed and did not appear to encode inactivating mutations. In contrast, expression of p16/INK4A was defective/absent in two cell lines and normal/slightly induced in the third cell line. To determine if defects were causative in maintaining the transformed phenotype, a p16/INK4A transgene was permanently transfected followed by selection and single cell cloning. CMT/p16 clones were characterized for transgene expression, p16 protein content and phenotype including proliferation rate, cell cycle phase distribution, contact inhibition, substrate dependent cell growth and cell morphology. All cell lines appeared unique yet clear indications of phenotype rescue due to p16/INK4A transgene complementation were observed suggesting that defects in p16 expression were present in all three. In some cases cellular senescence also appeared to be induced. These data provide evidence supporting p16/INK4A mutations as causative defects promoting transformation in canine mammary cancer and further characterizes tumor suppressor gene defects with functional consequences in these cells supporting their application as spontaneous animal models of human disease.
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PMID:Phenotype-rescue of cyclin-dependent kinase inhibitor p16/INK4A defects in a spontaneous canine cell model of breast cancer. 1913 Apr 92

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.
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PMID:The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis. 1971 24


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