Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the degree of the phosphorylation of ERKI/2, Akt-1 and p70 S6K in mouse skeletal and cardiac muscle was examined in vivo following an intraperitoneal injection of des IGF-I. Plasma levels of insulin, IGF-I and glucose were measured. The administration of des IGF-I had no effect on plasma levels of insulin, or IGF-I, but plasma glucose levels were decreased about 50% (p < 0.01). In both skeletal and cardiac muscle, des IGF-I increased the phosphorylation of Akt-1 at Ser 473 (p < 0.01) with no change in the phosphorylation of p44 and p42 MAP kinases at Thr202/Tyr204. The phosphorylation of p70 S6K at Thr421/Ser424 was increased in skeletal muscle (p < 0.01), but not in cardiac muscle. The phosphorylation of the nuclear transcription factor CREB phosphorylation at Ser 133 was not significantly changed in either skeletal or cardiac muscle. Des IGF-I increased the phosphorylation of the transcription factor FKHR in cardiac muscle only (p < 0.05). These data demonstrate that the administration of des IGF-I had differential effects on the activation of the MAP kinase and PI 3-kinase pathways in mouse skeletal and cardiac muscle.
Mol Cell Biochem 2002 Jul
PMID:Differential effects of des IGF-1 on Erks, AKT-1 and P70 S6K activation in mouse skeletal and cardiac muscle. 1219 Jan 9

Alveolar rhabdomyosarcoma is a pediatric disease specified by the recurrent chromosome translocations t(2;13) and t(1;13). These translocations result in the formation of the PAX3-FKHR and PAX7-FKHR fusion genes, which are thought to play a causal role in the genesis of this disease. Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown. We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas. By targeting FKHR cDNA sequences into the Pax3 locus of embryonic stem cells, we used these cells to generate mice carrying a Pax3-FKHR knock-in allele. Despite low expression of the knock-in allele, heterozygous offspring of Pax3-FKHR chimeric mice showed developmental abnormalities. These included intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. In addition, Pax3-FKHR heterozygous offspring displayed malformations of some but not all hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. We conclude that the Pax3-FKHR allele causes lethal developmental defects in knock-in mice but might be insufficient to cause muscle tumors.
Mol Cell Biol 2002 Oct
PMID:Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors. 1224 97

The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27(kip1) (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27(kip1)-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27(kip1) function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.
Mol Cell Biol 2002 Nov
PMID:Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. 1239 Nov 53

Medulloblastoma (D-341 MED) and rhabdomyosarcoma (TE-671) cell lines, which are resistant to either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of BCNU and O6-benzylguanine (O6-BG), were generated by serial escalation of BCNU. The activities of O6-alkylguanine-DNA alkyltransferase (AGT), glutathione-S-transferase (GST), and total glutathione (GSH) of the parental, BCNU-resistant (BR), and BCNU + O6-BG-resistant (OBR) cells were measured. No significant differences in GST activity or total GSH were seen between the parental, BR, and OBR cells of both TE-671 and D-341 MED. The AGT activities of D-341 MED (BR) and TE-671 (BR) were twice those of D-341 MED and TE-671, respectively, confirming the importance of this enzyme for BCNU resistance. The D-341 MED (OBR) cells did not exhibit any AGT activity, suggesting that another mechanism must play a role in the drug resistance. Fewer DNA interstrand cross-links (ICLs) were observed in D-341 MED (OBR) than in D-341 MED after 8 h BCNU (100-400 microM) treatment. However, the amounts of DNA ICLs observed in D-341 MED and D-341 MED (OBR) were stable after 24 h. Microarray analysis showed the increased expressions of several metallothionein genes and down-regulation of several proapoptotic genes. The AGT activity of TE-671 (OBR) was 223 fmol/mg when the cells were grown in 10 microM O6-BG and decreased to about half this value when the O6-BG concentration was increased 60 microM. The AGT cDNA of TE-671 (OBR) cells was cloned and found to contain a G-to-T transversion at codon 156, resulting in conversion of glycine to cysteine (G156C). In vitro mutagenesis has shown that the G156C AGT mutant is resistant to inactivation by O6-BG. Thus, the selection of a mutant AGT with decreased sensitivity to O6-BG is a significant contributing factor to BCNU + O6-BG resistance.
Mol Cancer Ther 2002 Jul
PMID:Mechanisms of resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea in human medulloblastoma and rhabdomyosarcoma. 1247 69

MDM2 inhibits transactivation properties of the tumor suppressor protein p53 by binding to and facilitating proteasomal degradation of p53. Because MDM2 targets p53 for degradation, it was anticipated that cells that overexpress MDM2 would not contain functional wild-type p53 (wtp53). However, p53 and MDM2 in cells with damaged DNA can become phosphorylated, and their binding to each other can become inhibited. Thus, p53 remains functional and induces apoptosis of damaged cells. Here we report the results of experiments designed to investigate whether MDM2 amplification and overexpression can inhibit p53-mediated chemosensitivity to DNA-damaging drugs. Two cell lines in which MDM2 is amplified, NB-1691 and Rh18, were transduced with an adenoviral expression vector for p53 (Ad.p53). Although functional wtp53 was detected, no change in chemosensitivity was observed, suggesting that endogenous wtp53 may have been active in the MDM2-amplified cells. The adenoviral vector Ad.MDM2 was used to generate MDM2 expression in a rhabdomyosarcoma cell line, Rh30-CI.27, engineered to express inducible wtp53. When p53 expression was induced, cells became chemosensitive to actinomycin D in the presence or absence of MDM2 expression; this result suggests that MDM2 cannot inhibit p53-mediated chemosensitivity. There was no evidence of a reduced amount of MDM2-p53 binding after drug exposure, but the remaining unbound wtp53 may be functional and capable of potentiating cytotoxicity. In conclusion, MDM2 expression is important in inhibiting p53 function during tumor development but not during the DNA damage-mediated cytotoxic response.
Mol Cancer Ther 2002 Oct
PMID:MDM2 does not influence p53-mediated sensitivity to DNA-damaging drugs. 1248 33

Recent studies suggested that the protection of cell apoptosis by AKT involves phosphorylation and inhibition of FKHR and related FOXO forkhead transcription factors and that androgens provide an AKT-independent cell survival signal in prostate cancer cells. Here, we report receptor-dependent repression of FKHR function by androgens in prostate cancer cells. Transcriptional analysis demonstrated that activation of the androgen receptor caused an inhibition of both wild-type FKHR and a mutant in which all three known AKT sites were mutated to alanines, showing that the repression is AKT independent. In vivo and in vitro coprecipitation studies demonstrated that the repression is mediated through protein-protein interaction between FKHR and the androgen receptor. Mapping analysis localized the interacting domains to the carboxyl terminus between amino acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand binding domain of the receptor. Further analysis demonstrated that the activated androgen receptor blocked FKHR's DNA binding activity and impaired its ability to induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle arrest. These studies identify a new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription and establish FKHR and related FOXO forkhead proteins as important nuclear targets for both AKT-dependent and -independent survival signals in prostate cancer cells.
Mol Cell Biol 2003 Jan
PMID:AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR. 1248 65

Transcription factors of the FoxO family in mammals are orthologues of the Caenorhabditis elegans forkhead factor DAF-16, which has been characterized as a target of insulin-like signalling. Three members of this family have been identified in rodents: FoxO1, FoxO3 and FoxO4, originally termed FKHR, FKHRL1 and AFX respectively. A number of in vitro studies have revealed that FoxOs are regulated through phosphorylation in response to insulin and related growth factors, resulting in their nuclear exclusion and inactivation. To clarify the mechanisms involved in the regulation of these factors in vivo, we investigated in the present study whether or not, and if so how, their mRNA levels in rat liver respond to the stimuli of several nutritional and hormonal factors. Imposed fasting for 48 h significantly elevated mRNA levels of FoxO1 (1.5-fold), FoxO3 (1.4-fold), and FoxO4 (1.6-fold). Refeeding for 3 h recovered the induced mRNA levels of FoxO1 and FoxO3 to the control levels, but did not affect that of FoxO4. FoxO1 and FoxO4 mRNA levels were proved to be highly reflective of their protein levels measured by Western immunoblotting. Of the three FoxO genes, FoxO4 only showed altered levels of mRNA (a 1.5-fold increase) in response to a protein-free diet. Streptozotocin-induced diabetes for 28 days decreased hepatic mRNA levels of FoxO1 and FoxO3 and increased the level of FoxO4 mRNA, but short-term (7 days) diabetes had fewer effects on the expression of these genes. Insulin replacement partially restored the FoxO1 and FoxO4 mRNA levels, but had no effect on the FoxO3 mRNA level. Daily administration for 1 week of dexamethasone, a synthetic glucocorticoid, increased the mRNA levels of FoxO1 (1.8-fold) and FoxO3 (2.4-fold). These results show that the FoxO genes respond differently to nutritional and hormonal factors, suggesting a new mechanism for the regulation of FoxO-dependent gene expression by these factors. Moreover, changes of FoxO1 and FoxO4 in the nucleus in response to fasting also suggest that the regulation of nucleus/cytoplasm translocation actually functions in vivo.
J Mol Endocrinol 2003 Apr
PMID:Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. 1268 47

Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to malignant transformation in human cancers, including those of the cutaneous epithelium. Accordingly, novel agents such as the EGFR tyrosine kinase inhibitor ZD1839 (Iressa), are promising, biologically based treatments that are currently in preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival. This study explored the effect of ZD1839 on the stimulation of p42/44 mitogen-activated protein kinase (MAPK) and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival, using immortalized keratinocytes (HaCaT cells) and cutaneous squamous cell carcinoma cells. The EGFR and a number of effector kinases (mitogen-activated protein extracellular signal-regulated kinase kinase 1 and 2, MAPK, Pak1, p38, c-JunNH(2)-terminal kinase and extracellular signal-regulated kinase 1) and cell survival proteins (AKT, FKHR, and c-Src) showed constitutive pathway activation in HaCaT and cutaneous squamous cell carcinoma cells. ZD1839 effectively inhibited EGFR and MAPK activation and Pak1 activity in exponentially growing cancer cells. ZD1839 also suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Y1068, MAPK phosphorylation on T402 and Y404, and Pak1 activity in a dose-dependent manner. In addition, ZD1839 blocked EGF-induced cytoskeleton remodeling, cell growth, and in vitro invasiveness of cancer cells and induced a differentiated squamous cell phenotype. These studies suggest that the EGFR-tyrosine kinase inhibitor ZD1839 may cause potent inhibition of the EGFR, MAPK, and Pak1 pathways, resulting in attenuation of transformed cell phenotypes and induced differentiation in human cancer cells deregulated in these growth factor receptor pathways.
Mol Cancer Ther 2003 Apr
PMID:Suppression of epidermal growth factor receptor, mitogen-activated protein kinase, and Pak1 pathways and invasiveness of human cutaneous squamous cancer cells by the tyrosine kinase inhibitor ZD1839 (Iressa). 1270 Feb 78

Rhabdomyosarcoma is a childhood tumor of the skeletal muscle lineage in which cells display defects in both biochemical and morphological aspects of differentiation. The immunoglobulin superfamily members CDO and BOC are components of a cell surface receptor that positively regulates myogenesis in vitro. Expression of Cdo and Boc in myoblast cell lines is downregulated by the ras oncogene, and forced re-expression of either Cdo or Boc can override ras-induced inhibition of myogenic differentiation [Kang et al., J Cell Biol 1998; 143:403-413; Kang et al., EMBO J 2002; 21:114-124]. The current study sought to test whether the promyogenic properties of CDO and BOC could be extended to a human rhabdomyosarcoma cell line, RD. Stable overexpression of CDO or BOC in RD cells led to enhanced expression of two markers of muscle cell differentiation, troponin T and myosin heavy chain, and to increased formation of elongated, myosin heavy chain-positive myotubes. These observations are consistent with the notion that CDO and BOC play a role in the inverse relationship between differentiation and transformation of cells in the skeletal muscle lineage.
Mol Carcinog 2003 May
PMID:Overexpression of the immunoglobulin superfamily members CDO and BOC enhances differentiation of the human rhabdomyosarcoma cell line RD. 1272 Feb 94

The ability to determine various functions of genes in an intact host will be an important advance in the postgenomic era. Intravital imaging of gene regulation and the physiological effect of the gene products can play a powerful role in this pursuit. Intravital epifluorescence microscopy has provided powerful insight into gene expression, tissue pH, tissue pO2, angiogenesis, blood vessel permeability, leukocyte-endothelial (L-E) interaction, molecular diffusion, convection and binding, and barriers to the delivery of molecular and cellular medicine. Multiphoton laser scanning microscopy (MPLSM) has recently been applied in vivo to overcome three drawbacks associated with traditional epifluorescence microscopy: (i) limited depth of imaging due to scattering of excitation and emission light; (ii) projection of three-dimensional structures onto a two-dimensional plane; and (iii) phototoxicity. Here, we use MPLSM for the first time to obtain high-resolution images of deep tissue lymphatic vessels and show an increased accuracy in quantifying lymphatic size. We also demonstrate the use of MPLSM to perform accurate calculations of the volume density of angiogenic vessels and discuss how this technique may be used to assess the potential of antiangiogenic treatments. Finally, high-speed MPLSM, applied for the first time in vivo, is used to compare L-E interactions in normal tissue and a rhabdomyosarcoma tumor. Our work demonstrates the potential of MPLSM to noninvasively monitor physiology and pathophysiology both at the tissue and cellular level. Future applications will include the use of MPLSM in combination with fluorescent reporters to give novel insight into the regulation and function of genes.
Mol Imaging
PMID:Conventional and high-speed intravital multiphoton laser scanning microscopy of microvasculature, lymphatics, and leukocyte-endothelial interactions. 1292 Aug 56


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