Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian cancer. We examined the production and function of GEP and report that: (1) GEP production is regulated by endothelin (ET-1), lysophosphatidic acid (LPA), and cAMP; (2) cAMP signals GEP production through exchange protein activated by cAMP (EPAC); (3) ET-1 and cAMP/EPAC induce GEP through ERK1/2; and (4) neutralization of GEP results in apoptosis. Exposure of HEY-A8 and OVCAR3 ovarian cancer cells to LPA and ET-1 yielded GEP production and secretion in a dose- and time-dependent fashion; neither stimulated significant concentrations of cAMP directly. Stimulation of cAMP production with pertussis and cholera toxin, or forskolin induced GEP in a PKA-independent fashion. EPAC, an intracellular cAMP receptor, is activated specifically by the cAMP analog, 8-CPT-2'-O-Me-cAMP (8-CPT); 8-CPT treatment stimulated GEP production and secretion. The MEK inhibitor, U0126, abrogated GEP production in response to ET-1 and 8-CPT, confirming involvement of MAPK. A partial inhibition of basal and stimulated GEP production was observed when cells were treated with a internal calcium chelator, BAPTA. Neutralizing anti-GEP antibody reversed basal as well as LPA, ET-1 and 8-CPT-induced ovarian cancer cell growth and induced apoptosis as demonstrated by caspase-3 and PARP cleavage, DNA fragmentation, and nuclear condensation. These results indicate that GEP is a growth and survival factor for ovarian cancer, induced by LPA and ET-1 and cAMP/EPAC through ERK1/2.
...
PMID:Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. 1604 62

Glial cell line-derived neurotrophic factor (GDNF), a known survival factor for neurons, has recently been shown to stimulate the migration of Schwann cells (SCs) and to enhance myelination. GDNF exerts its biological effects by activating the Ret tyrosine kinase in the presence of glycosylphosphatidylinositol-linked receptor, GDNF family receptor (GFR) alpha1. In Ret-negative cells, the alternative transmembrane coreceptor is the 140-kDa isoform of neural cell adhesion molecule (NCAM) associated with a non-receptor tyrosine kinase Fyn. We confirmed that GDNF, GFRalpha1 and NCAM are expressed in neonatal rat SCs. We found that GDNF induces an increase in the partitioning of NCAM and heparan sulfate proteoglycan agrin into lipid rafts and that heparinase inhibits GDNF-signaling in SCs. In addition to activation of extracellular signal-regulated kinases, and phosphorylation of cAMP response element binding protein, we found that cAMP-dependent protein kinase A and protein kinase C are involved in GDNF-mediated signaling in SCs. Although GDNF did not promote the differentiation of purified SCs into the myelinating phenotype, it enhanced myelination in neuron-SC cocultures. We conclude that GDNF utilizes NCAM signaling pathways to regulate SC function prior to myelination and at early stages of myelin formation.
...
PMID:Glial cell line-derived neurotrophic factor-induced signaling in Schwann cells. 1608 1

The secreted protein Hedgehog (Hh) plays an important role in metazoan development and as a survival factor for many human tumors. In both cases, Hh signaling proceeds through the activation of the seven-transmembrane protein Smoothened (Smo), which is thought to convert the Gli family of transcription factors from transcriptional repressors to transcriptional activators. Here, we provide evidence that Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners. We show that many of the commonly observed molecular events following Hh signaling are not transmitted in a linear fashion but instead are activated through two signals that bifurcate at Smo to independently affect activator and repressor pools of Ci.
...
PMID:Smoothened regulates activator and repressor functions of Hedgehog signaling via two distinct mechanisms. 1642 32

The prevention and therapy of neurodegenerative disorders in the elderly is one of the greatest challenges facing molecular medicine today. Alzheimer's is an excellent example of a disease being studied by many groups worldwide. Indeed, while many molecular details of this disorder have been elucidated in the last two decades, there are still no strictly causal therapies available. While certain symptomatic pharmacological treatments are frequently employed, current molecular medicine research is focused on central Alzheimer-associated biochemical changes to find the key switch that turns the detrimental Alzheimer process on. Although amyloid beta proteins and tau proteins are the focus of most investigations, intracellular signaling has recently gained a lot of attention as well. Signaling mediated by glycogen synthase kinase is intensively studied since it is a survival factor for neurons, is directly linked to Alzheimer-specific pathobiochemistry, and its activity can be modulated by well-known neuroprotective factors such as the female sex hormone estrogen.
...
PMID:The search for novel avenues for the therapy and prevention of Alzheimer's disease. 1655 Feb 51

For the bovine preimplantation embryo, insulin-like growth factor-I (IGF-I) is a survival factor that blocks the induction of apoptosis and reduces the decrease in development caused by heat shock. The first objective was to determine the signaling pathways whereby IGF-I acts to increase embryo cell number while inhibiting heat-shock induced apoptosis. Exposure of embryos to heat shock reduced cell number and increased percent apoptosis, but IGF-I increased cell number and blocked induction of apoptosis caused by heat shock. Actions of IGF-I to increase cell number were blocked by treatment with the mitogen activated protein kinase kinase (MAPKK) inhibitor PD 98059 whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002 had no effect. Conversely, LY 294002 but not PD 98059 blocked actions of IGF-I to inhibit induction of apoptosis caused by heat shock. The second objective was to determine whether IGF-I blocks effects of heat shock on development to the blastocyst stage by preventing apoptosis. Culture of embryos with IGF-I was effective in blocking the reduction in blastocyst development caused by heat shock-this action occurred even in the presence of LY 294002. Addition of another inhibitor of apoptosis, the caspase-3 inhibitor z-DEVD-fmk, did not mimic the protective effects of IGF-I on blastocyst development. Surprisingly, IGF-I was not effective in blocking the reduction in blastocyst development caused by heat shock when cultured with z-DEVD-fmk. In conclusion, the anti-apoptotic actions of IGF-I require PI3K signaling while actions to promote proliferation require MAPKK signaling. Moreover, actions of IGF-I to allow heat-shocked embryos to continue development to the blastocyst stage are independent of its anti-apoptotic effects.
...
PMID:Insulin-like growth factor-I promotes resistance of bovine preimplantation embryos to heat shock through actions independent of its anti-apoptotic actions requiring PI3K signaling. 1695 4

Ghrelin is an endogenous ligand for the GH secretagogue receptor, produced and secreted mainly from the stomach. Ghrelin stimulates GH release and induces positive energy balances. Previous studies have reported that ghrelin inhibits apoptosis in several cell types, but its antiapoptotic effect in neuronal cells is unknown. Therefore, we investigated the role of ghrelin in ischemic neuronal injury using primary hypothalamic neurons exposed to oxygen-glucose deprivation (OGD). Here we report that treatment of hypothalamic neurons with ghrelin inhibited OGD-induced cell death and apoptosis. Exposure of neurons to ghrelin caused rapid activation of ERK1/2. Ghrelin-induced activation of ERK1/2 and the antiapoptotic effect of ghrelin were blocked by chemical inhibition of MAPK, phosphatidylinositol 3 kinase, protein kinase C, and protein kinase A. Ghrelin attenuated OGD-induced activation of c-Jun NH2-terminal kinase and p-38 but not ERK1/2. We also investigated ghrelin regulation of apoptosis at the mitochondrial level. Ghrelin protected cells from OGD insult by inhibiting reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, ghrelin-treated cells showed an increased Bcl-2/Bax ratio, prevention of cytochrome c release, and inhibition of caspase-3 activation. Finally, in vivo administration of ghrelin significantly reduced infarct volume in an animal model of ischemia. Our data indicate that ghrelin may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.
...
PMID:Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. 1705 24

The cyclic AMP-response element-binding protein (CREB) is a bZIP family transcription factor implicated as an oncoprotein and neuron survival factor. CREB is activated in response to cellular stimuli, including cAMP and Ca(2+), via phosphorylation of Ser-133, which promotes interaction between the kinase-inducible domain (KID) of CREB and the KID-interacting domain of CREB-binding protein (CBP). We previously demonstrated that the interaction between CREB and CBP is inhibited by DNA-damaging stimuli through a mechanism whereby CREB is phosphorylated by the ataxia telangiectasia-mutated (ATM) protein kinase. We now show that the ATM phosphorylation sites in CREB are functionally intertwined with a cluster of coregulated casein kinase (CK) sites. We demonstrate that DNA damage-induced phosphorylation of CREB occurs in three steps. The initial event in the CREB phosphorylation cascade is the phosphorylation of Ser-111, which is carried out by CK1 and CK2 under basal conditions and by ATM in response to ionizing radiation. The phosphorylation of Ser-111 triggers the CK2-dependent phosphorylation of Ser-108 and the CK1-dependent phosphorylation of Ser-114 and Ser-117. The phosphorylation of Ser-114 and Ser-117 by CK1 then renders CREB permissive for ATM-dependent phosphorylation on Ser-121. Mutation of Ser-121 alone abrogates ionizing radiation-dependent repression of CREB-CBP complexes, which can be recapitulated using a CK1 inhibitor. Our findings outline a complex mechanism of CREB phosphorylation in which coregulated ATM and CK sites control CREB transactivation potential by modulating its CBP-binding affinity. The coregulated ATM and CK sites identified in CREB may constitute a signaling motif that is common to other DNA damage-regulated substrates.
...
PMID:Coregulated ataxia telangiectasia-mutated and casein kinase sites modulate cAMP-response element-binding protein-coactivator interactions in response to DNA damage. 1720 43

Acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Vasoactive intestinal peptide (VIP), a neuropeptide, may act as a survival factor for prostate cancer cells under androgen deprivation. However, the molecular mechanisms by which VIP promotes the androgen-independent growth of androgen-sensitive prostate cancer cells have not been addressed. We therefore investigated the biological effect and signal pathway of VIP in LNCaP cells, a prostate cancer cell line that requires androgens for growth. We showed that low nanomolar concentrations of VIP, acting through G(s)-protein-coupled VIP receptors, can induce LNCaP cell growth in the absence of androgen. Blockade of androgen-receptor (AR) in these cells by AR antagonist bicalutamide or by anti-AR small interfering RNA, inhibited the proliferative effect of VIP. In addition, VIP stimulated androgen-independent activation of AR with an EC(50) of 3.0 +/- 0.8 nM. We then investigated VIP-stimulated signaling events that may interact with the AR pathway in prostate cancer cells. VIP regulation of AR activation, mediated by VIP receptors, was protein kinase A (PKA)-dependent, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation contributes to VIP-mediated AR activation. Furthermore, PKA-dependent Rap1 activation is required for both ERK1/2 activation and androgen-independent AR activation in LNCaP cells upon VIP stimulation. Finally, we showed that VIP-induced AR activation was also present in prostate cancer CWR22Rv1 and PC3 cells transfected with the wild-type AR. Altogether, we demonstrate that VIP acting through its G(s)-protein-coupled receptors can cause androgen-independent transactivation of AR through a PKA/Rap1/ERK1/2 pathway, thus promoting androgen-independent proliferation of androgen-sensitive prostate cancer cells.
...
PMID:Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells. 1743 Sep 95

Over the past decade, parathyroid hormone-related protein (PTHrP) has been identified as a key survival factor for cells subjected to apoptotic stimuli. Its anti-apoptotic activity has been attributed to nuclear accumulation of the intact protein, or a synthetic peptide corresponding to its nuclear targeting sequence (NTS), which promotes rapid exit of nutrient deprived cells from the cell cycle. Intracellular PTHrP also inhibited apoptosis by blocking tumor necrosis factor alpha (TNFalpha)-induced apoptosis by blocking signaling from the "death receptor" and preventing damage to the mitochondrial membrane. In both cases, the anti-apoptotic activity was significantly reduced in the presence of a nuclear deficient form of PTHrP with a (88)K/E K/E.K/I(91) mutation in the NTS. The current work was undertaken to determine the mechanism by which nuclear PTHrP blocked mitochondrial-mediated apoptosis. Using sub-cellular fractionation and functional assays we showed that pre-treatment of HEK293 cells with exogenous NTS peptide before inducing apoptosis with TNFalpha was as effective as expression of the full-length protein in inhibiting apoptosis. Inhibition of apoptosis was associated with increased expression of protein kinase casein kinase 2 (CK2) and in sustained CK2 accumulation and activity in the nuclear fraction. In primary chondrogenic cells harvested from the limb buds of PTHrP(+/-) and PTHrP(-/-) embryonic mice, there was a dose-dependent decrease in CK2 expression and activity that correlated with increased susceptibility to apoptosis. Taken together the results indicate that nuclear accumulation of PTHrP effectively inhibits mitochondrial-mediated apoptosis through regulation of the expression, activity, and sub-cellular trafficking of CK2.
...
PMID:Parathyroid hormone-related protein (PTHrP) inhibits mitochondrial-dependent apoptosis through CK2. 1744 83

Tribbles, an atypical protein kinase superfamily member, coordinates cell proliferation, migration, and morphogenesis during the development of Drosophila and Xenopus embryos. Although Tribbles are highly conserved throughout evolution, the physiological functions of mammalian Tribbles family remain largely unclear. Here we report that human TRB2 is a pro-apoptotic molecule that induces apoptosis of cells mainly of the hematopoietic origin. TRB2 mRNA is selectively induced by removal of granulocyte macrophage colony-stimulating factor (GM-CSF) or interleukin-2 from human erythroleukemia-derived TF-1 cell line or activated primary CD4(+) T cells, respectively. It is, however, not induced by many other treatments that trigger apoptosis of these two cell types. Overexpression of TRB2 activates many apoptotic events observed in GM-CSF-deprived TF-1 cells, including loss of mitochondrial membrane potential, Mcl-1 cleavage/degradation, and activation of Bax and a number of caspases. Specific knockdown of TRB2 significantly suppresses GM-CSF deprivation-induced apoptosis and all apoptotic events mentioned above. Finally, we demonstrate that TRB2-induced cleavage and degradation of Mcl-1 are mediated via a caspase-dependent but proteasome-independent mechanism, and overexpression of Mcl-1 or its upstream activator Akt can markedly overcome the apoptogenic effect of TRB2. Altogether, these results suggest that the TRB2-Mcl-1 axis plays an important role in survival factor withdrawal-induced apoptosis of TF-1 cells.
...
PMID:Survival factor withdrawal-induced apoptosis of TF-1 cells involves a TRB2-Mcl-1 axis-dependent pathway. 1754 67


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

---