Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Integrin-linked kinase (ILK) is a focal adhesion serine/threonine protein kinase that is emerging as a key signaling protein functioning at one of the early convergence points of integrin- and growth factor-signaling pathways. ILK binds to PINCH through the N-terminal ankyrin (ANK) repeat domain and the PINCH binding is crucial for focal adhesion localization of ILK. The ILK-PINCH interaction also connects ILK to Nck-2, an SH2-SH3-containing adaptor protein that interacts with components of growth factor and small GTPase signaling pathways. The kinase activity of ILK is regulated by both cell adhesion and growth factors in a phosphoinositide 3-kinase (PI3K)-dependent manner. ILK phosphorylates downstream targets such as protein kinase B (PKB, also known as Akt) and glycogen synthase kinase 3 (GSK-3) and regulates their activities. Overexpression of ILK in epithelial cells leads to striking morphological changes mimicking epithelial-mesenchymal transition, including upregulation of integrin-mediated fibronectin matrix assembly and downregulation of cell-cell adhesions. Furthermore, ILK regulates nuclear translocation of (beta)-catenin and gene expression, and promotes cell cycle progression and tumor formation. Recent genetic studies in Drosophila melanogaster and Caenorhabditis elegans have shown that lack of expression of ILK or PINCH results in phenotypes resembling those of integrin-null mutants, which demonstrates that ILK and PINCH are indispensable for integrin function during embryonic development.
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PMID:Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction. 1057 98

PTEN phosphatase is a tumor suppressor gene that dephosphorylates phosphatidylinositol phosphates. PTEN restrains the function of a major antiapoptotic and survival pathway involving phosphoinositide 3-kinase and Akt kinase. Our purpose was to find out whether apoptotic inducers affect the expression of PTEN in cerebellar granule neurons and neuroblastoma 2a cells (Neuro-2a). PTEN mRNA expression showed a major 5.5-kb and a lower abundance 2.5-kb transcripts. In Neuro-2a cells, serum withdrawal induced a prominent, continuous decrease both in 5.5- and 2.5-kb transcripts of PTEN mRNA. Simultaneously, the expression level of 56-kDa PTEN protein decreased in Neuro-2a cells. The decrease in PTEN expression precedes apoptotic changes observed after serum withdrawal. On the contrary, okadaic acid and etoposide only slightly affected the expression of PTEN although they induce a prominent apoptosis in Neuro-2a cells. In cerebellar granule neurons, okadaic acid treatment induced a prominent increase in PTEN mRNA expression after 6-h treatment, both at the 5.5- and 2.5-kb transcripts. The early response in PTEN mRNA expression disappeared in 5.5-kb transcripts already at 12 h and in the case of 2.5-kb transcripts it lasted up to 24 h. Potassium deprivation, known to induce apoptosis in cerebellar granule cells, did not affect PTEN mRNA expression but together with serum deprivation induced a clear decrease in the 5. 5-kb PTEN transcripts. It seems that the changes in PTEN expression level and neuronal apoptosis are not related to each other in general but the expression of PTEN phosphatase seems to regulate certain apoptotic signals affecting phosphoinositide 3-kinase function.
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PMID:Regulation of PTEN expression in neuronal apoptosis. 1058 15

Whereas the tumor acidic extracellular pH plays a crucial role in the invasive process, the mechanism(s) behind this acidification, especially in low nutrient conditions, are unclear. The regulation of the Na(+)/H(+) exchanger (NHE) and invasion by serum deprivation were studied in a series of breast epithelial cell lines representing progression from non-tumor to highly metastatic cells. Whereas serum deprivation reduced lactate production in all three cells lines, it inhibited NHE activity in the non-tumor cells and stimulated it in the tumor cells with a larger stimulation in the metastatic cells. The stimulation of NHE in the tumor cell lines was the result of an increased affinity of the internal H(+) regulatory site of the NHE without changes in sodium kinetics or expression. Serum deprivation conferred increased cell motility and invasive ability that were abrogated by specific inhibition of the NHE. Inhibition of phosphoinositide 3-kinase by overexpression of a dominant-negative mutant or wortmannin incubation inhibited NHE activity and invasion in serum replete conditions while potentiating the serum deprivation-dependent activation of the NHE and invasion. These results indicate that the up-regulation of the NHE by a phosphoinositide 3-kinase-dependent mechanism plays an essential role in increased tumor cell invasion induced by serum deprivation.
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PMID:Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na(+)/H(+) exchange, motility, and invasion induced by serum deprivation. 1068 10

Several guanine nucleotide exchange factors for the Rho family of GTPases that induce activation by exchanging GDP for GTP have been identified. One of these is the tumor invasion gene product Tiam1, which acts on Rac1. In this study, we demonstrate that platelet-derived growth factor (PDGF) and lysophosphatidic acid induce the translocation of Tiam1 to the membrane fraction of NIH 3T3 fibroblasts in a time-dependent manner. Previously, we have shown that Tiam1 is phosphorylated by protein kinase C (PKC) and calcium/calmodulin kinase II (CaMK II) after stimulation with agonists. Here we show, by pretreatment of cells with kinase inhibitors, that CaMK II, but not PKC, is involved in the membrane translocation of Tiam1. Addition of the calcium ionophore ionomycin alone induced the translocation of Tiam1. However, the cell-permeable diacylglycerol oleoylacetylglycerol was without effect and did not enhance the effect of ionomycin. These data further indicated a role for CaMK II and not PKC. Inhibition of phosphoinositide 3-kinase by wortmannin had little effect on the translocation of Tiam1. The role of phosphorylation was further studied by comparing the phosphorylation pattern of Tiam1 in the membranes versus whole cell Tiam1. PDGF-induced phosphorylation of membrane-associated Tiam1 occurred more rapidly than that of the total Tiam1 pool, and CaMK II, but not PKC, played a significant role in this process. Furthermore, by using the p21-binding domain of PAK-3, we show that PDGF, but not lysophosphatidic acid, activates Rac1 in vivo and that this activation involves CaMK II and PKC, but not 3-phosphoinositides. Our results indicate that Tiam1 is translocated to and phosphorylated at membranes after agonist stimulation and that CaMK II, but not PKC, is involved in this process. Also, these kinases are involved in the activation of Rac in vivo.
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PMID:Translocation of the Rac1 guanine nucleotide exchange factor Tiam1 induced by platelet-derived growth factor and lysophosphatidic acid. 1073 27

The PTEN gene is a tumor suppressor localized in the frequently altered chromosomal region 10q23. The tumor suppressor function of the PTEN protein (PTEN) has been linked to its ability to dephosphorylate the lipid second-messenger phosphatidylinositol 3,4, 5-trisphosphate and phosphatidylinositol 3,4-bisphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway. The PTEN protein consists of an amino-terminal phosphatase domain, a lipid binding C2 domain, and a 50-amino-acid C-terminal domain (the "tail") of unknown function. A number of studies have shown that the tail is dispensable for both phosphatase activity and blocking cell growth. Here, we show that the PTEN tail is necessary for maintaining protein stability and that it also acts to inhibit PTEN function. Thus, removing the tail results in a loss of stability but does not result in a loss of function because the resultant protein is more active. Furthermore, tail-dependent regulation of stability and activity is linked to the phosphorylation of three residues (S380, T382, and T383) within the tail. Therefore, the tail is likely to mediate the regulation of PTEN function through phosphorylation.
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PMID:Phosphorylation of the PTEN tail regulates protein stability and function. 1086 58

Cowden disease is an autosomal dominant disorder associated with an increased risk of developing benign and malignant tumors in many organ systems including the breast, thyroid, skin, central nervous system and gastrointestinal tract. Recently, germline mutations in PTEN (also known as MMAC1/TEP1) have been identified on chromosome 10q23 in Cowden disease patients. This gene is suggested to be a tumor suppressor gene, because coding-region mutations are observed in several tumor specimens or tumor cell lines. PTEN functions as a dual specificity phosphatase and lipid phosphatase. PTEN appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell growth and survival. Furthermore, PTEN may also inhibit cell migration, spreading, and focal adhesion by interacting with the focal adhesion kinase.
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PMID:[Cowden disease]. 1092 27

PTEN (phosphatase and tensin homolog deleted on chromosome ten), a recently discovered tumor suppressor gene, appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell proliferation and cell survival by dephosphorylating the phosphatidylinositol 3,4,5-triphosphate. To date, 110 germline PTEN mutations have been reported in patients affected with two tumor predisposing syndromes, each having overlapping clinical features: Cowden disease and Bannayan-Riley-Ruvalcaba syndrome. These germline mutations are scattered along the length of the gene, with the exception of exon 9 (no mutation reported) and exon 1 (only two mutations reported). A mutational hot spot is found in exon 5, which encodes the phosphatase catalytic core motif, and recurrent mutations are also found at CpG dinucleotides suggesting deamination-induced mutations. PTEN has also been found to be defective in a large number of sporadic human tumors. In this article, 332 somatic point mutations of PTEN, occurring in primary tumors or metastasis, have been reviewed. Somatic PTEN mutations are more particularly involved in two types of human cancers: endometrial carcinomas and glioblastomas. In most cases, these somatic mutations result in protein inactivation and, as with germline mutations, recurrent somatic mutations are found in CpG dinucleotides. A mutagenesis by insertion-deletion in repetitive elements is however specifically observed in endometrial carcinomas.
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PMID:Mutations of the human PTEN gene. 1092 32

A rodent oncogenic mutant of the Neu receptor tyrosine kinase is a useful experimental model because overexpression of the respective receptor, namely HER2/ErbB-2, in human malignancies is associated with relatively aggressive diseases. Here we show that the oncogenic form of Neu is constitutively associated with the product of the c-cbl proto-oncogene and is part of a large complex that includes the phosphoinositide 3-kinase and Shc. Ectopic expression of c-Cbl, a ubiquitin-protein isopeptide ligase specific to activated tyrosine kinases, causes rapid removal of Neu from the cell surface and severely reduces signaling downstream of oncogenic Neu. c-Cbl-induced down-regulation of Neu involves covalent attachment of ubiquitin molecules and requires the carboxyl-terminal domain of Neu. The negative effect of c-Cbl is antagonized by v-Cbl, a virus-encoded oncogenic truncated form of c-Cbl. In an in vivo model, infection of a Neu-transformed neuroblastoma with a c-Cbl-encoding retrovirus caused enhanced down-regulation of Neu and correlated with tumor retardation. Our results implicate c-Cbl in negative regulation of Neu and offer a potential target for treatment of HER2/ErbB-2-positive human malignancies.
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PMID:c-Cbl is a suppressor of the neu oncogene. 1094 Feb 98

PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G(1) arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27(KIP1) protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.
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PMID:Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. 1107 96

PTEN/MMAC1/TEP-1 (PTEN) tumor suppressor and androgen receptor play important roles in prostatic tumorigenesis by exerting opposite effects on homeostasis of prostatic epithelium. Here, we describe a mutual repression and selective dominance between PTEN and the androgen receptor (AR) in the growth and the apoptosis of prostatic cancer cells. On the one hand, PTEN and an inhibitor of phosphoinositide 3-kinase repressed the transcriptional activity of the AR as well as androgen-induced cell proliferation and production of prostate-specific antigen. On the other hand, androgens protected prostate cancer cells from PTEN-induced apoptosis in an AR-dependent manner. Whereas the repression of the transcriptional activity of the AR by PTEN is likely to involve the down-regulation of AKT, androgens protected prostate cancer cells from PTEN-induced apoptosis without an effect on AKT activity, demonstrating a differential involvement of AKT in the interaction between PTEN and the AR. Our data suggest that the loss of PTEN function may induce tumorigenesis through unopposed activity of the AR as well as contribute to the resistance of prostate cancers to androgen ablation therapy.
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PMID:Antagonism between PTEN/MMAC1/TEP-1 and androgen receptor in growth and apoptosis of prostatic cancer cells. 1127 45


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