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

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder, in which multiple genetic abnormalities cooperate in the malignant transformation of thymocytes. About 20% of pediatric T-ALL cases are characterized by TLX3 expression due to a cryptic translocation t(5;14)(q35;q32). Although a number of collaborating genetic events have been identified in TLX3 rearranged T-ALL patients (NOTCH1 mutations, p15/p16 deletions, NUP214-ABL1 amplifications), further elucidation of additional genetic lesions could provide a better understanding of the pathogenesis of this specific T-ALL subtype. In this study, we used array-CGH to screen TLX3 rearranged T-ALL patients for new chromosomal imbalances. Array-CGH analysis revealed five recurrent genomic deletions in TLX3 rearranged T-ALL, including del(1)(p36.31), del(5)(q35), del(13)(q14.3), del(16)(q22.1) and del(19)(p13.2). From these, the cryptic deletion, del(5)(q35), was exclusively identified in about 25% of TLX3 rearranged T-ALL cases. In addition, 19 other genetic lesions were detected once in TLX3 rearranged T-ALL cases, including a cryptic WT1 deletion and a deletion covering the FBXW7 gene, an U3-ubiquitin ligase that mediates the degradation of NOTCH1, MYC, JUN and CyclinE. This study provides a genome-wide overview of copy number changes in TLX3 rearranged T-ALL and offers great new challenges for the identification of new target genes that may play a role in the pathogenesis of T-ALL.
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PMID:Cooperative genetic defects in TLX3 rearranged pediatric T-ALL. 1818 24

Despite significant advances in the detection and treatment of hepatocellular carcinoma, the prognosis of patients with hepatocellular carcinoma remains very poor, in part due to the high incidence of recurrence. This study was aimed at identifying a prognostic indicator of recurrence in patients with hepatocellular carcinoma. We retrospectively analyzed CpG island hypermethylation of the p14, p15, p16, GSTP1, integrin alpha4, SYK, and CDH1 genes in fresh-frozen tissues from 265 patients with hepatocellular carcinoma using the methylation-specific PCR. The expression levels of p16 and p53 were evaluated by immunohistochemistry. CpG island hypermethylation was detected in 6% for p14, 21% for p15, 67% for p16, 75% for GSTP1, 23% for integrin alpha4, 12% for SYK, and 57% for CDH1. Recurrence was observed in 102 (38%) of the 265 patients. There was no association between the risk for recurrence and hypermethylation of any gene studied. However, p16 methylation was associated with a poor survival after surgery for recurrent stage I to II hepatocellular carcinomas (hazard ratio, 4.05; 95% confidence interval, 1.15-14.20; P = 0.03). In addition, the hazard of failure after recurrence was about 3.80 (95% confidence interval, 1.03-14.20; P = 0.04) times higher in patients with p16 methylation than in those without. Negative expression of p16 at a protein level was also associated with poor survival in recurrent stage I to II hepatocellular carcinomas, but p53 expression did not have a synergistic effect on the poor prognosis. In conclusion, the present study suggests that p16 methylation may be associated with a poor prognosis in recurrent early-stage hepatocellular carcinomas.
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PMID:Promoter hypermethylation of the p16 gene is associated with poor prognosis in recurrent early-stage hepatocellular carcinoma. 1872 30

Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16(INK4A) and p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph(+)]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph(+) ALLs) but are not seen in more indolent Ph(+) chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph(+) ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCR-ABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph(+) ALL, loss of INK4-ARF in Ph(+) ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy.
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PMID:The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias. 1902 87

Abnormalities in the signal transducer and activator of transcription (STAT) pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT5 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated. To investigate the role of STAT5 in CRC progression, we depleted STAT5 with a small interfering RNA (siRNA). Our results demonstrate that STAT5 is involved in CRC cell growth, cell cycle progression, invasion and migration through regulation of gene expression, such as Bcl-2, p16(ink4a), p21(waf1/cip1), p27(kip1), E-cadherin, the focal adhesion kinase (FAK), vascular endothelial growth factor (VEGF) and matrix metalloproteinases. In addition, immunohistochemical staining reveals upregulation of STAT5 during CRC tumorigenesis. Moreover, phospho-STAT5 (pSTAT5) is predominantly localized in the cytoplasm of adenomas cells and colon adenocarcinoma cells, but primarily presented in the nucleus of normal colonic epithelium cells. Thus, pSTAT5 protein is shuttled from the nucleus to the cytoplasm in the oncogenesis of CRC, suggesting that activated STAT5 may also have cytoplasmic functions. In support of this hypothesis, we found that STAT5 formed a complex with p44/42 MAPK and SAPK/JNK in CRC cells, suggesting cross talk between STAT5 signaling and the MAPK pathway in the development of human CRC. Our findings illustrate the biological significance of STAT5 signaling in CRC progression, and provide novel evidence that intervention in STAT5 signaling may have potential therapeutic value in the prevention of human colorectal cancer.
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PMID:Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells. 1929 7

Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92-100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16(INKA)/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called "p53 signatures"), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
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PMID:Insights into endometrial serous carcinogenesis and progression. 1929 1

The t(2;14)(p16;q32) has been reported previously in only 12 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The clinicopathologic features have been incompletely described. We describe 6 new cases of CLL/SLL with t(2;14)(p16;q32). All had marrow involvement, 4 had absolute lymphocytosis, 4 had lymphadenopathy, and 3 had hepatosplenomegaly. All showed atypical lymphocyte morphologic features with plasmacytoid differentiation and irregular nuclei; 3 had increased prolymphocytes. Flow cytometry demonstrated typical immunophenotypes in 5 and an atypical immunophenotype in 1. All expressed ZAP70; 5 assessed showed unmutated IgV(H) genes. Karyotyping identified t(2;14)(p16;q32) as the sole abnormality in 1, primary abnormality in 2, and part of a complex karyotype in 3. Fluorescence in situ hybridization analysis revealed BCL11A/IgH rearrangement in all. After chemotherapy, 3 patients died of disease and 3 were alive with disease (median follow-up, 80 months). We conclude that CLL/SLL with t(2;14) (p16;q32) and BCL11A/IgH rearrangement is characterized by atypical morphologic features and unmutated IgV(H) genes.
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PMID:Chronic lymphocytic leukemia With t(2;14)(p16;q32) involves the BCL11A and IgH genes and is associated with atypical morphologic features and unmutated IgVH genes. 1936 25

The adaptor protein Crk mediates intracellular signaling related to cell motility and proliferation and is implicated in human tumorigenesis. The role of Crk in the growth of human sarcoma has remained unclear, however. The present study shows that Crk-induced activation of Src and subsequent signaling by p38 mitogen-activated protein kinase (MAPK) contribute to the enhanced proliferation of human synovial sarcoma cells. Depletion of Crk by RNA interference markedly inhibited proliferation of the synovial sarcoma cell lines HS-SYII, SYO-1, and Fuji as well as prevented anchorage-independent growth. Conversely, reconstitution with CrkII by authentic small interfering RNA-resistant Crk gene restored proliferation in Crk-silenced SYO-1 cells. Crk-depleted synovial sarcoma cells manifested enhanced transcriptional activity and expression of the p16(INK4A) gene, resulting in their accumulation in G(1) phase of the cell cycle. In response to hepatocyte growth factor stimulation, Crk prominently induced the tyrosine phosphorylation of Grb2-associated binder 1 through activation of Src and focal adhesion kinase, and the Src family kinase inhibitor PP2 almost completely inhibited the proliferation of SYO-1 cells. Crk also induced the phosphorylation of p38 MAPK, and SB203580, a p38 MAPK-specific inhibitor, increased expression of p16(INK4A) gene in SYO-1 cells. Furthermore, SB203580 or depletion of p38 MAPK by small interfering RNA suppressed both the phosphorylation of Akt triggered by hepatocyte growth factor and the proliferation of SYO-1 cells. These results suggest that Crk promotes proliferation of human synovial sarcoma cells through activation of Src and its downstream signaling by a novel p38 MAPK-Akt pathway, with these signaling molecules providing potent new targets for molecular therapeutics.
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PMID:Adaptor protein Crk induces Src-dependent activation of p38 MAPK in regulation of synovial sarcoma cell proliferation. 1973 74

3,5,3',4',5'-pentamethoxystilbene (MR-5) is a synthetically methoxylated analogue of resveratrol and has been suggested to have antitumor activity because of structural similarity to resveratrol. Herein, we investigate the antiproliferative effect of MR-5 in human breast cancer MCF-7 cells and demonstrate that MR-5 had a more potent inhibition on cell growth compared with resveratrol and other methoxylated derivatives. Exploring the growth-inhibitory mechanisms of MR-5, we found that it is accompanied by G1 cell cycle arrest, which coincides with a marked inhibition of G1 cell cycle regulatory proteins, including decreased cyclins (D1/D3/E) and cyclin-dependent kinases (CDK2/4/6) and increased CDK inhibitors (CKIs) such as p15, p16, p21, and p27. Furthermore, the increase in CKI levels by MR-5 resulted in a concomitant increase in their interactions of CDK4 and CDK2, along with a strong inhibition in CDK4 kinase activity and the accumulation of hypophosphorylated Rb. MR-5 also modulated some critical kinase activities related to cell cycle regulation, including Akt, mitogen-activated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and focal adhesion kinase (FAK) in MCF-7 cells. In total, our results demonstrate that MR-5 affects multiple cellular targets that contribute to its antiproliferative activity in MCF-7 cells and provide novel information for synthetic chemists to design new antitumor agents with introduction of methoxylated group(s) in the basic compound.
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PMID:3,5,3',4',5'-pentamethoxystilbene (MR-5), a synthetically methoxylated analogue of resveratrol, inhibits growth and induces G1 cell cycle arrest of human breast carcinoma MCF-7 cells. 1991 42

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer deaths worldwide. Proper classification and early identification of HCC and precursor lesions is essential to the successful treatment and survival of HCC patients. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into three subgroups: those with mutant TCF1/HNF1 alpha gene, those with mutant beta-catenin, and those without mutations in either of these loci. Hepatic adenomas with alpha-catenin mutations have a significantly greater risk for malignant transformation in comparison with the other two subgroups. Telangiectatic focal nodular hyperplasia has now been reclassified as telangiectatic adenoma due to the presence of non-random methylation patterns, consistent with the monoclonal origin which is similar to hepatic adenoma and HCC. HCC precursor lesions demonstrate unique molecular alterations of HSP70, CAP2, glypican 3, and glutamine synthetase that have proven useful in the histologic diagnosis of early HCC. Though specific genetic alterations depend on HCC etiology, the main proteins affected include cell membrane receptors (in particular tyrosine kinase receptors) as well as proteins involved in cell signaling (specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways), cell cycle regulation (i.e. p53, p16/INK4, cyclin/cdk complex), invasiveness (EMT, TGF-beta) and DNA metabolism. Advances in gene expression profiling have provided new insights into the molecular genetics of HCC. HCCs can now be stratified into two clinically relevant groups: Class A, the low survival subclass (overall survival time 30.3+/- 8.02 months), shows strong expression signatures of cell proliferation and antiapoptosis genes (such as PNCA and cell cycle regulators CDK4, CCNB1, CCNA2, and CKS2) as well as genes involving ubiquitination and sumoylation; Class B, the high survival subclass (overall survival time 83.7 +/-10.3 months), does not have the above expression signature. In fact, insights into HCC-specific alterations of signal transduction pathways and protein expression patterns have led to the development of new therapeutic agents with molecular targets such as EGFR, VEGF, or other multi-kinase inhibitors. In the future, these specific molecular alterations in HCC can potentially serve as diagnostic tools, prognostic markers, and/or therapeutic targets with the potential to alter clinical outcomes.
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PMID:Molecular genetics of hepatocellular neoplasia. 2018 87

DNA methyltransferase inhibitors (MTIs) have recently emerged as promising chemotherapeutic or preventive agents for cancer, despite their poorly characterized mechanisms of action. The present study shows that DNA methylation is integral to the regulation of SH2-containing protein tyrosine phosphatase 1 (SHP1) expression, but not for regulation of suppressors of cytokine signalling (SOCS)1 or SOCS3 in colorectal cancer (CRC) cells. SHP1 expression correlates with down-regulation of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3/STAT5) signalling, which is mediated in part by tyrosine dephosphorylation events and modulation of the proteasome pathway. Up-regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2'-deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling. We demonstrate that 5-aza-dc suppresses growth of CRC cells, and induces G2 cell cycle arrest and apoptosis through regulation of downstream targets of JAK2/STAT3/STAT5 signalling including Bcl-2, p16(ink4a), p21(waf1/cip1) and p27(kip1). Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells. Our results demonstrate that 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling. This study represents the first evidence towards establishing a mechanistic link between inhibition of JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells that may lead to the use of MTIs as a therapeutic intervention for human colorectal cancer.
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PMID:Inhibition of DNA methyltransferase induces G2 cell cycle arrest and apoptosis in human colorectal cancer cells via inhibition of JAK2/STAT3/STAT5 signalling. 2019 86


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