Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colon cancer progression is associated with the activation of protein kinase C (PKC), the downregulation of functional E-cadherin and an increased expression of the serine protease urokinase (u-PA) and its receptor (u-PAR). HT29-M6 intestinal epithelial cells represent an in vitro model to study colon cancer progression. These cells are induced to scatter and to invade by phorbol esters. Using proteolytic and cell signaling inhibitors, we show that HT29-M6 cells require plasminogen for the acquisition of the scattering response to PMA. Our results indicate that, prior to inducing a state of competency for plasminogen-dependent scattering, PMA triggers an ordered succession of events where upregulation of the activity of u-PA precedes proteolysis of u-PAR and active degradation of the extracellular matrix (ECM). These events poise HT29-M6 cells to a scatter-competent state that allows the subsequent localized proteolytic activation of plasminogen to plasmin, required for the execution of scattering. Finally, we show that, in addition to its enzymatic activity directed at the degradation of ECM, plasmin generates an intracellular signal resulting in the phosphorylation of ERK 1/2. For a full motogenic activity, plasmin requires this signal since the use of a MEK inhibitor (PD98059) specifically blocks the plasmin-dependent phase of cell scattering. Our observations suggest that plasmin exerts a dual role in PMA-induced scattering of HT29-M6 cells, one directed extracellularly to promote proteolysis of the ECM and one directed to generate intracellular signaling.
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PMID:Requirement of the enzymatic and signaling activities of plasmin for phorbol-ester-induced scattering of colon cancer cells. 1663 Nov 61

The membrane mucin Muc4 has been shown to alter cellular behavior through both anti-adhesive effects on cell-cell and cell-extracellular matrix interactions and its ability to act as an intramembrane ligand for the receptor tyrosine kinase ErbB2. The ERK pathway is regulated by both cell-matrix and cell-cell adhesion. An analysis of the effects of Muc4 expression on ERK phosphorylation in mammary tumor and epithelial cells, which exhibit both adhesion-dependent growth and contact inhibition of growth, showed that the effects are density dependent, with opposing effects on proliferating cells and contact-inhibited cells. In these cells, cell-matrix interactions through integrins are required for activation of the ERK mitogenesis pathway. However, cell-cell interactions via cadherins inhibit the ERK pathway. Expression of Muc4 reverses both of these effects. In contact-inhibited cells, Muc4 appears to activate the ERK pathway at the level of Raf-1; this activation does not depend on Ras activation. The increase in ERK activity correlates with an increase in cyclin D(1) expression in these cells. This abrogation of contact inhibition is dependent on the number of mucin repeats in the mucin subunit of Muc4, indicative of an anti-adhesive effect. The mechanism by which Muc4 disrupts contact inhibition involves a Muc4-induced relocalization of E-cadherin from adherens junctions at the lateral membrane of the cells to the apical membrane. Muc4-induced abrogation of contact inhibition may be an important mechanism by which tumors progress from an early, more benign state to invasiveness.
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PMID:Membrane mucin Muc4 induces density-dependent changes in ERK activation in mammary epithelial and tumor cells: role in reversal of contact inhibition. 1689 13

We present a case of an unusual tumor that occurred in the perianal area of a 64-year-old woman. Clinical investigation revealed no tumor elsewhere. The lesion was removed and the patient is alive without signs of metastasis or recurrence 5.5 years after surgery. Histopathologically, the neoplasm was composed of single-cell cords of uniform round to ovoid cells intermixed with round to elongated tubules showing decapitation secretion at the luminal border. The tubules were mainly composed of a single cell layer, but focally multilayered epithelium (without evidence of myoepithelial cell differentiation) was seen as well as discrete cribriform structures and intraluminal bridges. Overall, the cell cord component slightly dominated over the tubular component, and the two were intermixed. A vague targetoid arrangement of the cell cords was seen focally. Immunohistochemically, the tumor cells in both components reacted positively for E-cadherin, 34betaE12, estrogen receptors and progesterone receptor and were negative for HER2/neu (c-erbB-2). There was no evidence of myoepithelial cell differentiation with calponin. We believe that the present case is best classified as mammary type tubulolobular carcinoma and, given the location, the origin in anogenital mammary-like glands most likely.
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PMID:Mammary type tubulolobular carcinoma of the anogenital area: report of a case of a unique tumor presumably originating in anogenital mammarylike glands. 1693 66

Erythropoietin (Epo) is the major regulator of differentiation, proliferation and survival of erythroid progenitors, but the Epo-induced changes in gene expression that lead to these effects are not fully understood. The aim of this study was to examine how Epo, via activation of phosphatidylinositol 3-kinase (PI3K)/Akt, exerts its role in the development of erythroid progenitors from CD34+ cells, and to identify early Epo target genes in human erythroid progenitors. In CD34+ progenitor cells, Epo alone was able to induce cell cycle progression as demonstrated by upregulation of cyclin D3, E and A leading to hyperphosphorylation of the retinoblastoma protein (RB). These effects were completely counteracted by the PI3K inhibitor LY294002. Furthermore, enforced expression of an activated form of Akt kinase highly augmented Epo-induced erythropoiesis. Fluorescent-activated cell sorting (FACS)-sorted CD34+CD71+CD45RA-GPA- erythroid progenitors stimulated with Epo in the presence or absence of LY294002 were subjected to gene expression profiling. Several novel target genes of Epo were identified, and the majority were regulated in a PI3K-dependent manner, including KIT (CD117) and CDH1 (E-cadherin). FACS analysis of Epo-stimulated erythroid progenitors showed that the increased mRNA expression of KIT and CDH1 was accompanied by an induction of the corresponding proteins CD117 and E-cadherin.
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PMID:PI3K/Akt-dependent Epo-induced signalling and target genes in human early erythroid progenitor cells. 1696 83

Progression of colorectal cancer (CRC) involves spatial and temporal occurrences of epithelial-mesenchymal transition (EMT), whereby tumour cells acquire a more invasive and metastatic phenotype. Subsequently, the disseminated mesenchymal tumour cells must undergo a reverse transition (mesenchymal-epithelial transition, MET) at the site of metastases, as most metastases recapitulate the pathology of their corresponding primary tumours. Importantly, initiation of tumour growth at the secondary site is the rate-limiting step in metastasis. However, investigation of this dynamic reversible EMT and MET that underpins CRC morphogenesis has been hindered by a lack of suitable in vitro models. To this end, we have established a unique in vitro model of CRC morphogenesis, which we term LIM1863-Mph (morphogenetic). LIM1863-Mph cells spontaneously undergo cyclic transitions between two-dimensional monolayer (migratory, mesenchymal) and three-dimensional sphere (carcinoid, epithelial) states. Using RNAi, we demonstrate that FZD7 is necessary for MET of the monolayer cells as loss of FZD7 results in the persistence of a mesenchymal state (increased SNAI2/decreased E-cadherin). Moreover, FZD7 is also required for migration of the LIM1863-Mph monolayer cells. During development, FZD7 orchestrates either migratory or epithelialization events depending on the context. Our findings strongly implicate similar functional diversity for FZD7 during CRC morphogenesis.
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PMID:Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids. 1701 32

Some examples of lobular carcinoma in situ (LCIS) may be composed in part of signet ring cells. Such proliferations have been considered examples of pleomorphic LCIS based on pathological features of the more conventional component. However, the occurrence of LCIS composed entirely of signet ring cells is extraordinarily rare. This report describes an example of an in situ proliferation that was composed almost entirely (>95%) of signet ring cells, which was unassociated with an invasive carcinoma and which showed comedo-type necrosis. There was only focal lobulocentric distention by lesional cells, as is typical of classic LCIS. However, discrete, ductal-type cross-sectional profiles showed a purely intraepithelial proliferation of remarkably discohesive signet ring cells. The signet ring cells had intermediate-grade nuclear atypia, no significant mitotic activity and were positive for mucicarmine and PAS stains (the latter with and without diastase predigestion). The cells displayed marked immunoreactivity for high-molecular-weight keratin (stained by 34beta E12 antibody), MUC1, gross cystic disease fluid protein-15, cytokeratin 7 and were negative for cytokeratin 20, E-cadherin, progesterone receptor and HER2/neu. It is concluded that this is an example of a purely signet ring variant of pleomorphic LCIS.
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PMID:Pleomorphic lobular carcinoma in situ of the breast composed almost entirely of signet ring cells. 1704 Feb 92

The recent finding that lobular, and not ductal intraepithelial neoplasia (DIN) displays loss of E-cadherin expression has greatly facilitated the categorization of a large proportion of morphologically ambiguous intraepithelial neoplasias into ductal or lobular types. One reason for such morphologic ambiguity is the presence of comedo-type necrosis within an intraepithelial lesion that otherwise shows archetypal cytologic and architectural features of lobular intraepithelial neoplasia (LIN). The clinicopathologic features of 18 such cases are described in this report. These 18 cases of classic LIN were accumulated from the recent databases of 6 institutions. All cases, by definition, showed no expression of E-cadherin. The 18 patients, all women, were 41 to 85 years of age (mean 61.3). The lesions were initially identified in an excisional biopsy or mastectomy in 12 cases and in an incisional/core biopsy in the remaining 6 cases. An associated invasive carcinoma was present in 12 (67%) of 18 cases (7 classic lobular, 1 pleomorphic lobular, 1 ductal, 1 mixed lobular and ductal, 1 tubular, and 1 case with ductal and lobular carcinomas as separate foci). The average age of the 6 patients with pure LIN (ie, LIN without an invasive component (62.5 y) was not significantly different from the 12 patients in which there was an invasive component (60.7 y) (P = 0.78). The lesions had associated calcifications, typically within the necrotic foci, in 10 (55%) of 18 cases. Immunoreactivity for estrogen receptor, progesterone receptor (in >10% of lesional cells), and high-molecular weight keratin was present in 17/18 (94%), 15/18 (83%) and 17/18 (94%) of cases, respectively. Overexpression of HER2/neu, as assessed immunohistochemically, was absent in all 15 cases available for such evaluation. Foci of DIN, separate from the lobular lesions, were present in 6 (33%) of 18 cases. LIN with necrosis seems to occur at an older age than classic LIN, is commonly associated with invasive carcinoma and is significantly more frequently associated with lobular than ductal invasive carcinoma. When present without an invasive component, it may be mistaken for DIN 2 (grade 2 ductal carcinoma in situ). Although the necrosis suggests a ductal phenotype for these intraepithelial proliferations, architectural and cytologic features, high-molecular weight keratin[+], estrogen receptor[+], progesterone receptor[+], and human epidermal growth factor receptor 2 /neu[-] immunoprofile, frequent association with invasive lobular carcinoma, and lack of immunoreactivity for E-cadherin, strongly suggests that these lesions are within the morphologic spectrum of lobular neoplasia. Long-term follow-up studies are required to define the true natural history of these lesions. However, because classic LIN with necrosis is apparently rare in its pure form, reexcision is recommended when this lesion is detected in isolation in a core biopsy.
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PMID:Lobular intraepithelial neoplasia [lobular carcinoma in situ] with comedo-type necrosis: A clinicopathologic study of 18 cases. 1706 87

Prognosticators evaluating survival in breast cancer vary in significance in respect to lymph node status. Studies have shown e.g. that HER2/neu immunohistochemistry or HER2/neu gene amplification analysis do perform well as prognosticators in lymph node positive (LN +) patients but are less valuable in lymph node negative (LN -) patients. We collected data from different studies and tried to evaluate the relative significance of different prognosticators in LN+/LN- patient groups. In LN+ patients HER2/neu and E-cadherin immunohistochemistry were the statistically most significant prognosticators followed by proliferation associated features (mitotic counts by SMI (standardised mitotic index) or MAI (mitotic activity index), or S-phase fraction). Bcl-2 immunohistochemistry was also significant but p53 and cystatin A had no significance as prognosticators. In LN- patients proliferation associated prognosticators (SMI, MAI, Ki-67 index, PCNA immunohistochemistry, S-phase fraction) are especially valuable and also Cathepsin D, cystatin A, and p53 are significant, but HER2/neu or bcl-2, or E-cadherin less significant or without significance. We find that in studies evaluating single prognosticators one should distinguish between prognosticators suitable for LN+ and LN- patients. This will allow the choice of best prognosticators in evaluating the prospects of the patient. The distinction between LN+ and LN- patients in this respect may also be of special value in therapeutic decisions.
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PMID:Lymph node status as a guide to selection of available prognostic markers in breast cancer: the clinical practice of the future? 1709 54

Tubulolobular carcinoma is a type of mammary carcinoma that displays an admixture of invasive tubules and lobular-like cells. Previous reports have shown it to share clinical similarities to lobular carcinoma, whereas more recent studies have shown it to be E-cadherin positive. The aim of the current study was to further explore the immunophenotype of tubulolobular carcinoma, and to document its natural behavior. Nineteen cases of tubulolobular carcinoma and 10 cases each of tubular and lobular carcinoma were retrieved for comparison analysis. Immunohistochemistry was performed with antibodies against estrogen receptor, progesterone receptor, HER2/neu, 34betaE12, E-cadherin, and the catenins. Twenty-five percent of patients with tubulolobular carcinoma presented with greater than stage I disease, compared to 0 and 60% of patients with tubular and lobular carcinoma, respectively. Two patients with tubulolobular carcinoma had tumor recurrence, one of whom also developed metastasis. The majority of all carcinomas were estrogen and progesterone receptor positive. E-cadherin displayed membranous staining in all tubular and tubulolobular carcinomas, and was negative in all lobular carcinomas. Half of each carcinoma subtype displayed granular cytoplasmic 34betaE12 immunoreactivity. alpha-Catenin exhibited partial or complete membranous staining in all tubulolobular and tubular carcinomas, and was negative in all lobular carcinomas. beta-Catenin displayed membranous staining in tubulolobular and tubular carcinomas, whereas all lobular carcinomas had coarse cytoplasmic immunoreactivity. p120 and gamma-catenin displayed membranous staining in 100% of tubulolobular and tubular carcinomas and cytoplasmic staining in 100% of lobular carcinomas. Tubulolobular carcinoma of the breast is thus a distinct type of mammary carcinoma that displays both tubular and lobular patterns histologically but displays the membranous E-cadherin/catenin complex characteristic of the ductal immunophenotype. Tubulolobular carcinoma appears to be more aggressive than tubular carcinoma, as 16% of patients had lymph node metastases, although all were alive at a mean follow-up of 40 months.
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PMID:The ductal phenotypic expression of the E-cadherin/catenin complex in tubulolobular carcinoma of the breast: an immunohistochemical and clinicopathologic study. 1865 93

HER2 (also known as ErbB2) is a transmembrane tyrosine kinase whose surface overexpression is linked to tumorigenesis and poor prognosis in breast cancer patients. beta-catenin is a substrate of this kinase, and HER2-dependent phosphorylation of tyrosine 654 leads to dissociation of the E-cadherin-beta-catenin membrane complex and increased Wnt signaling. beta-catenin-mediated Wnt signaling promotes proliferation and invasion of breast cancer cells. In this study, we show that HER2 binds to beta-catenin and that geldanamycin (GA), a drug that destabilizes HER2 protein, causes rapid depletion of HER2, thereby disrupting its association with beta-catenin in SKBr3 human breast cancer cells. Interestingly, GA did not affect the stability of beta-catenin protein, but altered its subcellular localization, driving it out of the nucleus and increasing its association with E-cadherin. Importantly, the change in subcellular localization of beta-catenin was also associated with a significant decrease in proliferation and motility of GA-treated breast cancer cells. Moreover, GA treatment led to reduced expression of the Wnt signaling target and cell cycle-promoting gene cyclin D1, providing a potential mechanism for the reduced proliferation. In conclusion, GA treatment suppressed tumorigenicity in the human breast cancer cell line SKBr3, at least in part through destabilization of the HER2 oncoprotein and repression of the Wnt/beta-catenin signaling pathway. These findings provide evidence for the clinical importance of GA in treatment of HER2 overexpressing breast cancers.
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PMID:Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/beta-catenin signaling in HER2 overexpressing human breast cancer cells. 1714 83


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