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)

Previous work has demonstrated that chromosome 11 is trisomic or shows a duplicated region encompassing the E1/E2 band of chromosome 11 in 90% of v-abl/myc-induced plasmacytomas (Wiener et al. 1995). In the present report, we have studied BALB/c PreB lymphocytes that were immortalized by v-abl and stably transfected with a conditional MycER vector (Mai et al. 1999). These cells, termed PreB ABL/MYC, showed changes in the E1/E2 bands of chromosome 11 that are similar to those reported previously for v-abl/myc-induced plasmacytomas. This was shown by the use of chromosome painting, SKY, FISH and mBAND. Our findings suggest that the Pre-B ABL/MYC cells may be used to analyse the genetic changes affecting chromosome 11 that are associated with v-abl/myc-dependent tumorigenesis in mouse B cells.
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PMID:Rearrangements of the telomeric region of mouse chromosome 11 in Pre-B ABL/MYC cells revealed by mBANDing, spectral karyotyping, and fluorescence in-situ hybridization with a subtelomeric probe. 1570 16

Constitutive activation of the JAK/STAT3 pathway is a major contributor to oncogenesis. In the present study, structure-activity relationship (SAR) studies with five cucurbitacin (Cuc) analogs, A, B, E, I, and Q, led to the discovery of Cuc Q, which inhibits the activation of STAT3 but not JAK2; Cuc A which inhibits JAK2 but not STAT3 activation; and Cuc B, E, and I, which inhibit the activation of both. Furthermore, these SAR studies demonstrated that conversion of the C3 carbonyl of the cucurbitacins to a hydroxyl results in loss of anti-JAK2 activity, whereas addition of a hydroxyl group to C11 of the cucurbitacins results in loss of anti-STAT3 activity. Cuc Q inhibits selectively the activation of STAT3 and induces apoptosis without inhibition of JAK2, Src, Akt, Erk, or JNK activation. Furthermore, Cuc Q induces apoptosis more potently in human and murine tumors that contain constitutively activated STAT3 (i.e., A549, MDA-MB-435, and v-Src/NIH 3T3) as compared to those that do not (i.e., H-Ras/NIH 3T3, MDA-MB-453, and NIH 3T3 cells). Finally, in a nude mouse tumor xenograft model, Cuc Q, but not Cuc A, suppresses tumor growth indicating that JAK2 inhibition is not sufficient to inhibit tumor growth and suggesting that the ability of Cuc Q to inhibit tumor growth is related to its anti-STAT3 activity. These studies further validate STAT3 as a drug discovery target and provide evidence that pharmacological agents that can selectively reduce the P-STAT3 levels in human cancer cells result in tumor apoptosis and growth inhibition.
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PMID:Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. 1573 20

Since identifying a transmissible agent responsible for tumorigenesis in chickens, the v-Src oncogene, significant progress has been made in determining the functions of its cellular homologue. c-Src is the product of the SRC gene and has been found both over-expressed and highly activated in a number of human cancers. In fact the relationship between c-Src activation and cancer progression is significant. Furthermore c-Src may play a role in the acquisition of the invasive and metastatic phenotype. In this review we will summarize some of the latest evidence for the role of c-Src in tumorigenesis and particularly in human tumor progression. In this review, specifically, we will address growth signals, adhesion, migration, invasion, angiogenesis and functional genomics.
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PMID:Novel insights into c-Src. 1585 60

The clinical significance of phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression and the correlation between the expression of PTEN and phosphorylation of protein kinase B (PKB/AKT) in human hepatocellular carcinoma (HCC) were investigated. The expression of PTEN and phospho-AKT was detected by SP immunohistochemical technique and Western blotting in 35 cases of HCC, 15 cases of liver cirrhosis and 8 cases of normal tissues. The correlation between the expression of PTEN and PKB/AKT in HCC was analyzed. The results showed that the positive expression of PTEN in HCC (62.9%, 0.085 +/- 0.021) was significantly lower than that in liver cirrhosis and normal tissues (P < 0. 01). The expression level of PTEN was related to the differentiation degree of HCC and the status of metastasis (P < 0.05). Western blotting revealed a significant inverse correlation between PTEN and phospho-AKT (r = -0.818, P < 0.01). These results demonstrated that down-regulation or loss of PTEN, which may not be able to effectively inhibit the hyper-phosphorylation of PKB/AKT, might play an important role in tumorigenesis and progression of HCC.
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PMID:Correlation between loss of PTEN expression and PKB/AKT phosphorylation in hepatocellular carcinoma. 1593 6

The JAK-STAT signal transduction cascade participates in various cellular processes, including immune response, cell replication, differentiation and oncogenesis. Here, we report that this cascade is induced in two human myeloid HL-60 leukemia cell variants by the granulocyte differentiation inducer dimethyl sulfoxide (DMSO) and macrophage differentiation inducer phorbol 12-myristate 13-acetate (PMA). DMSO and PMA also induced the expression and catalytic activity of 2'-5' oligoadenylate synthetase (2-5A synthetase), a known interferon (IFN) inducible enzyme. The HL-60 cell variants included HL-205, which is susceptible to DMSO- and PMA-induced differentiation, and HL-525, which is susceptible to DMSO- but not to PMA-induced differentiation. Treatment of HL-205 and HL-525 cells with DMSO and HL-205 cells with PMA-induced JAK1 phosphorylation, JAK1/STAT1 association, formation of STAT1-STAT2 heterodimers, and the binding of the active IFN stimulating growth factor 3 (ISGF3) to the IFN-stimulated response element (ISRE) fragment isolated from the 2-5A synthetase promoter. These events were either reduced or absent in the resistant HL-525 cells treated with PMA. Taken together, our data implicate the above signaling cascade in DMSO- and PMA-induced 2-5A synthetase expression and catalytic activity in the HL-60 cell system.
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PMID:JAK-STAT signaling involved in phorbol 12-myristate 13-acetate- and dimethyl sulfoxide-induced 2'-5' oligoadenylate synthetase expression in human HL-60 leukemia cells. 1597 43

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the balanced reciprocal translocation t (9:22). The resulting fusion gene, the BCR-ABL, is responsible for oncogenesis. Imatinib mesylate is a novel molecule, which inhibits the protein product of this fusion gene and hence has been used in the treatment of CML. The present study evaluates 174 patients with CML treated with imatinib mesylate. Of these 174 patients, 97 were in chronic phase, 47 in accelerated phase and 30 patients had blast crisis. Patients in chronic phase received imatinib mesylate in the dose of 400-mg daily, while those in accelerated phase and blast crisis received 600 to 800 mg daily. Of the 97 patients with chronic phase, 49 patients (50.5%) achieved a major (major + complete) cytogenetic response. Of the 47 patients in accelerated phase, 10 patients (21.3%) achieved a major cytogenetic response and in 30 patients with blast crisis, 7 (23.3%) achieved a major cytogenetic response. Dermatitis, mucositis, neutropenia and thrombocytopenia were some of the major toxicities. Of interest, 121 of the 174 patients (69.5%) developed generalized hypopigmentation. We conclude that imatinib mesylate is a safe and effective first-line therapy for chronic myeloid leukemia.
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PMID:Imatinib mesylate in chronic myeloid leukemia: a prospective, single arm, non-randomized study. 1598 13

Cyclooxygenase (COX) enzymes catalyze the biosynthesis of eicosanoids, including prostaglandin (PG) F2alpha. PGF2alpha exerts its autocrine/paracrine function by coupling to its G protein-coupled receptor [F-series-prostanoid (FP) receptor] to initiate cell signaling and target gene transcription. In the present study, we found elevated expression of COX-2 and FP receptor colocalized together within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF2alpha-FP receptor interaction in modulating COX-2 expression and PGF2alpha biosynthesis using an endometrial adenocarcinoma cell line stably transfected with the FP receptor cDNA (FPS cells). PGF2alpha-FP receptor activation rapidly induced COX-2 promoter, mRNA, and protein expression in FPS cells. These effects of PGF2alpha on the expression of COX-2 could be abolished by treatment of FPS cells with an FP receptor antagonist (AL8810) and chemical inhibitor of ERK1/2 kinase (PD98059), or by inactivation of ERK1/2 signaling with dominant-negative mutant isoforms of Ras or ERK1/2 kinase. We further confirmed that elevated COX-2 protein in FPS cells could biosynthesize PGF2alpha de novo to promote a positive feedback loop to facilitate endometrial tumorigenesis. Finally, we have shown that PGF2alpha could potentiate tumorigenesis in endometrial adenocarcinoma explants by inducing the expression of COX-2 mRNA.
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PMID:A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F2alpha synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signaling pathway. 1608 31

Oncogenesis results from a progressive accumulation of genetic aberrations consequent to a complex interplay between carcinogenic factors and innate infidelity of DNA surveillance mechanisms. Although the development of genetic aberrations is random, those conferring survival advantages are selected for in a Darwinian manner, thus allowing continuous adaptation to selection pressures. Chromosomal aberrations are a prominent manifestation of genetic damage, which can be closely linked with tumor behavior and outcome as exemplified by curative treatment of chronic myelogenous leukemia resulting from targeting the BCR-ABL translocation. In the case of head and neck squamous cell carcinomas (HNSCC), chromosomal changes are detectable at all stages of tumor development, providing excellent opportunities for genomic prognostication and therapy. Several studies have shown that the overall genomic profile of HNSCC is highly consistent, but individual tumors vary significantly in their complement of genetic alterations, thereby confounding clinical correlation. The application of modern genetic and bioinformatic analytic approaches has facilitated the identification of critical genomic changes in HNSCC, many of which have been linked to clinical outcome. These genetic aberrations represent excellent targets for novel therapeutics, but require validation. The initiation of phase III trials evaluating the therapeutic utility of genetic aberrations suggests a promising future for genome-based treatment of HNSCC.
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PMID:Chromosomal aberrations in squamous cell carcinomas of the upper aerodigestive tract: biologic insights and clinical opportunities. 1609 Nov 11

Mammalian Notch-1 is part of an evolutionarily conserved family of transmembrane receptors best known for involvement in cell fate decisions. Mutations that result in Notch-1 activation result in T-lineage oncogenesis. In other cell lineages, however, studies have indicated that cooperation with cellular signaling pathways, such as Ras, is necessary for Notch-mediated oncogenesis and in some settings, Notch-1 has been reported to function as a tumor suppressor. In order to test the hypothesis that the Notch-1 pathway exhibits cross-talk with Ras/Raf/MEK/ERK, the constitutively active cytoplasmic portion of Notch-1 was introduced into 293 HEK fibroblasts via retroviral transduction. ERK-1,-2 activation was markedly increased in cells expressing constitutively active Notch-1. These cells exhibited a more rounded morphology as compared to 293 cells transduced with an empty vector or parental 293 cells. These observations correlated with decreased total and phosphorylated focal adhesion kinase protein (FAK). Subsequent examination of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) revealed that total and phosphorylated PTEN protein was elevated in cells expressing constitutively active Notch-1. Loss of Akt phosphorylation was also observed in cells bearing activated Notch-1. Two potential binding sites for the Notch effector CBF-1 were identified in the human PTEN promoter sequence. A PTEN promoter luciferase reporter exhibited increased activity in the presence of Notch-1 signaling. These data indicate that Notch-1 can participate in cross-talk with other signaling pathways such as Ras/Raf/MEK/ERK through the regulation of the PTEN tumor suppressor.
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PMID:Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1. 1609 76

Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencing of retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronic-phase (CP, n=140) and the blast crisis (BC, n=47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (P<0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (P<0.0001) and c-MET gene antisense transcription (P<0.0001), and was significantly associated with high levels of BCR-ABL (P=0.02) and DNMT3b4 (P=0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P=0.004) or imatinib (P=0.034) and progression-free survival (P=0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML.
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PMID:Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia. 2338 83


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