Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of several intracellular proteins involved in cell cycle control and tumour growth is regulated by the ubiquitin-dependent multicatalytic protease complex (proteasome). We report that proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leucinal (PSI) was cytotoxic on most human myeloid leukaemia cell lines at IC50 doses ranging from 5 to 25 nmol/l. Additionally, PSI pre-treatment enhanced cytotoxicity by taxol and cisplatinum. PSI was more active on leukaemic than on normal CD34(+) bone marrow progenitors because the 50% growth inhibition of colony-forming unit granulocyte macrophage (CFU-GM) from cases of chronic myelogenous leukaemia (CML) and normal subjects was achieved by 15 nmol/l and 50 nmol/l PSI respectively. PSI killed cells by apoptosis as revealed by ultrastructural changes, nuclear DNA fragmentation, cleavage of poly (ADP-ribose) polymerase (PARP) and of beta-catenin, and was antagonized by ectopic expression of Bcl-2 but not by inactivating mutations of p53. This event was associated with a slight accumulation of Bcl-2, a decrease of Bax but no changes in Bcl-X(L) protein expression at any time point. In Ph(+) cell lines BCR-ABL protein was only down-regulated after 48 h of treatment with 10 nmol/l PSI. Altogether, these results indicate that PSI, alone or in association with other cytotoxic agents, has anti-tumour activity against myeloid malignancies and is more effective on leukaemic than on normal haematopoietic progenitor cells.
 ...
PMID:The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI. 1132 92

The alkylating agent methylmethanesulfonate (MMS) activates the c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 mitogen-activated protein kinase (p38MAPK) pathways via different mechanisms of action. Activation of p38MAPK by MMS involves the pp125 focal adhesion kinase-related tyrosine kinase RAFTK and the MAPK kinase 3. The way in which MMS can activate JNK/SAPK has not been elucidated. Here we describe the identification by differential display of human mitogen-activated gene-6 (MIG-6) as a novel MMS-inducible gene. Induction of MIG-6 by MMS was found in human diploid skin fibroblasts and in simian virus 40-transformed skin fibroblasts, indicating that the enhanced expression of MIG-6 after MMS-treatment did not require p53. The signal leading to activation of MIG-6 appeared to be independent of DNA damage. High MIG-6 expression was found in the liver, lung, and placenta. MIG-6 is an adapter protein that binds to the activated form of cdc42Hs and to 14-3-3 proteins, thereby activating JNK/SAPKs. Our results suggest that activation of JNK/SAPKs by MMS may involve the induction of MIG-6.
 ...
PMID:Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate. 1142 82

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
 ...
PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98

The Mdm2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. To regulate p53, Mdm2 must gain nuclear entry, and the mechanism that induces this is now identified. Mitogen-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, the Akt/PKB serine-threonine kinase, results in phosphorylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus. Pharmacological blockade of PI3-kinase/Akt signaling or expression of dominant-negative PI3-kinase or Akt inhibits nuclear entry of Mdm2, increases cellular levels of p53, and augments p53 transcriptional activity. Expression of constitutively active Akt promotes nuclear entry of Mdm2, diminishes cellular levels of p53, and decreases p53 transcriptional activity. Mutation of the Akt phosphorylation sites in Mdm2 produces a mutant protein that is unable to enter the nucleus and increases p53 activity. The demonstration that PI3-kinase/Akt signaling affects Mdm2 localization provides insight into how this pathway, which is inappropriately activated in many malignancies, affects the function of p53.
 ...
PMID:A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. 1157 54

PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
 ...
PMID:Regulation of PTEN transcription by p53. 1154 34

Uridine phosphorylase (UPase) is a key enzyme in the pyrimidine salvage pathway. It reversibly catalyzes the catabolism of uridine to uracil; controls the homeostatic regulation of uridine concentration in plasma and tissues; and plays a role in the intracellular activation of 5-fluorouracil. We cloned the murine UPase gene promoter, a 1703-bp fragment, and determined the transcription initiation sites located at +1 and +92 bp of the cDNA sequence. Through transient expression analysis of the 5'-flanking region of UPase gene, we have evaluated the promoter activity for a series of fragments with 5'- to 3'-deletion in murine breast cancer EMT-6 cells and immortalized murine fibroblast NIH 3T3 cells. Cotransfection of the UPase promoter constructs (from -1619 to -445) containing p53 binding motif with the wild-type p53 construct resulted in a significant reduction of luciferase activity; however, this effect disappeared with the additional deletion of the -445 to -274 sequence to suggest the existence in this promoter region of a putative p53 recognition element. Similar cotransfection in murine embryo fibroblasts p53-/- confirmed the inhibitory role of p53 on the UPase promoter activity. The specificity of the interaction is demonstrated by nuclear protein-specific binding to the putative p53 recognition sequence using gel mobility shift assay and DNase I footprinting analysis. These data indicate the UPase gene is a novel target of p53, and its expression is down-regulated by p53 at the promoter level.
 ...
PMID:p53-dependent suppression of uridine phosphorylase gene expression through direct promoter interaction. 1155 67

In the past ten years a wealth of fundamental knowledge delineating the molecular mechanism(s) of apoptosis has emerged, and can now be exploited to identify novel apoptotic modulators for the treatment of cancer. Two distinct yet complimentary classes of non-genotoxic agonists that can selectively kill tumor cells are discussed; agents that target 'classical' and 'atypical' apoptotic signaling pathways. The goal of agents targeting classical apoptosis and survival pathways is to directly modulate key apoptotic regulators such as Bcl-2, Akt/PKB, and p53. The aim of agents targeting atypical apoptotic pathways is to target signaling cascades whose inhibition remains non-lethal in normal cells, yet is suicidal in tumor cells. Such compounds presently under development include inhibitors of heat shock protein 90, histone deacetylases and HMG-CoA reductase. Both classes of apoptotic modulators have merit and identification of additional agonists of this nature will provide the many diverse cytotoxic agents that are required to combat the many diseases we call cancer.
 ...
PMID:Apoptosis modulators as cancer therapeutics. 1156 48

WISP-1 (Wnt-1-induced secreted protein) was identified as an oncogene regulated by the Wnt-1-beta-catenin pathway. WISP-1 belongs to the CCN family of growth factors, which are cysteine-rich, heparin-binding, secreted proteins associated with the extracellular matrix, and can interact with cellular integrins. Expression of WISP-1 in some cells results in transformation and tumorigenesis. Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. It also is demonstrated that WISP-1 can prevent cells from undergoing apoptosis following DNA damage through inhibition of the mitochondrial release of cytochrome c and up-regulation of antiapoptotic Bcl-X(L). Furthermore, the results show that WISP-1 protects cells from p53-dependent cell death, but not Fas-ligand activated cell death, suggesting that there may be cross talk between the tumor suppressor protein p53 and WISP-1 signaling pathways. WISP-1 acts to block cell death at a late stage in the p53-mediated apoptosis pathway.
 ...
PMID:WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. 1178 44

BCR-ABL confers apoptotic resistance to a range of genotoxic agents, and this protection is mediated in part by prolonging the G2 checkpoint. The p53 tumour suppressor protein regulates the transcription of regulatory genes involved in cell cycle arrest and apoptosis. To investigate the effect of p53 on the BCR-ABL-mediated G2M checkpoint response, we transiently transfected the BCR-ABL-positive, p53-negative cell line K562 with wild-type human p53. The p53-transfected cells showed a decreased ability to arrest in G2 and an increase in apoptosis in response to etoposide treatment, relative to the control mock-transfected cells. p53-transfected and control cells were treated with etoposide and trapped at mitosis with nocodazole. The mitotic index of p53-transfected cells was higher than that of the control cells, which suggests that p53 abrogates the G2 checkpoint response to etoposide treatment in K562 cells. We found that the expression of the cell cycle checkpoint protein Chk1 was reduced in the etoposide-treated p53-transfected cells by 24 h, and this correlated with a reduction in the extent of etoposide-induced phosphorylation of CDK1 at tyrosine 15 (Y15). We conclude, therefore, that p53 overrides the strong G2 checkpoint response to etoposide in K562 cells, by directly or indirectly downregulating Chk1 expression, which, in turn, contributes to the proapoptotic effect of p53.
 ...
PMID:p53-mediated downregulation of Chk1 abrogates the DNA damage-induced G2M checkpoint in K562 cells, resulting in increased apoptosis. 1184 47

The p53 tumor suppressor protein and the Akt/PKB kinase play important roles in the transduction of pro-apoptotic and anti-apoptotic signals, respectively. We provide evidence that conflicting signals transduced by Akt and p53 are integrated via negative feedback between the two pathways. On the one hand, the combination of ionizing radiation and survival factor deprivation, which leads to rapid apoptosis of IL-3 dependent DA-1 cells, entails a caspase- and p53-dependent destruction of Akt. This destruction of Akt is not a secondary consequence of apoptosis, since it is not seen when the same cells are triggered to undergo apoptosis under different conditions. On the other hand upon serum stimulation, when Akt becomes active and enhances cell survival, phosphorylation occurs at an Akt consensus site (serine 166) within the Mdm2 protein, a key regulator of p53 function. Taken together, our findings suggest that depending on the balance of signals, p53-dependent downregulation of Akt may promote an irreversible commitment to apoptotic cell death, whereas effective recruitment of Akt by appropriate survival signals may lead to activation of Mdm2, inactivation of p53, and eventually inhibition of p53-dependent apoptosis.
 ...
PMID:Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. 1185 Aug 50


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