Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that cytoskeletal reorganization (CSR) induced by pharmacological reagents such as colchicine or cytochalasins can up-regulate the urokinase-type plasminogen activator (uPA) gene via the Ras/Erk signaling pathway. In this present study using the small interfering RNA technique, we have found that ShcA adapter proteins play a rather active role in CSR-induced Erk activation, contrary to their mostly redundant role in other signaling pathways, e.g. growth factor-induced Erk activation, where Grb2 can bind directly to the receptor tyrosine kinase and activate Erk in the absence of ShcA. ShcA knockdown abolished CSR-induced activation of both Erk and the uPA promoter. Expression of small interfering RNA-escaping silent mutants of p52 or p46 but not p66 ShcA isoform efficiently rescued CSR-induced Erk activation. Moreover, we have shown that phosphorylation of either Tyr-239/Tyr-240 or Tyr-313 in p52(ShcA) can mediate CSR-induced Erk activation equally well. In a quest for molecules upstream of ShcA in this signaling, we found that CSR-induced ShcA tyrosine phosphorylation, its association with Grb2, Erk activation, and uPA gene expression were all dependent on Rho kinase, p38 mitogen-activated protein kinase, and Src. In summary, we have found a novel, non-redundant role for ShcA in contrast to its redundant role in many other signaling pathways.
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PMID:Non-redundant role of Shc in Erk activation by cytoskeletal reorganization. 1457 54

The Ets family of transcription factors regulate expression of multiple genes involved in tumour progression. The aim of this study was to investigate the expression of Ets-1 in a large panel of human breast cancers and relate its levels to the parameters of tumour progression and metastasis. Using RT-PCR, Ets-1 mRNA was detected in 30 out of 42 (71%) fibroadenomas and 131 out of 179 (73%) primary breast carcinomas. Similarly, levels of Ets-1 mRNA were not significantly different in fibroadenomas and primary breast carcinomas. Using Western blotting, four forms of the Ets-1 protein were detected, that is, p33, p42, p51 and p52. Levels of both p51 and p52 but not p33 and p42 were present at significantly higher levels in the carcinomas compared to the fibroadenomas (for p51, P<0.007; for p52, P<0.02; Mann-Whitney U-test). Levels of p52, p51 and p33 correlated significantly with uPA protein levels (P<0.01), while only levels of p52 correlated significantly with HER-2/neu protein levels (P<0.01). Using immunohistochemistry, Ets-1 was found predominantly in tumour cells, but was also detected in some stromal cells surrounding tumour islands. We conclude that, while at the mRNA level, Ets-1 was found at similar levels in fibroadenomas and primary breast carcinomas, higher protein levels were detected in the cancers compared to the benign specimens. Since p52, p51 and p33 correlate with uPA levels, these forms of Ets-1 may play a role in breast cancer metastasis.
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PMID:Overexpression of the Ets-1 transcription factor in human breast cancer. 1633 4

The Ets family of transcription factors regulate the expression of multiple genes involved in tumour formation and progression. The aim of this work was to test the hypothesis that the expression of Ets2 in breast cancers was associated with parameters of tumour progression and metastasis. Using reverse-transcriptase polymerase chain reaction (RT-PCR), Ets2 mRNA was detected in 69% of 181 breast carcinomas, 63% of 43 fibroadenomas and 47% of 43 specimens of normal breast tissue. Levels were significantly higher in carcinomas compared with normal breast tissue (P = 0.006). Using Western blotting, Ets2 protein was found to migrate as two bands with molecular masses of 52 kDa (p52) and 54kDa (p54). Levels of both proteins were significantly higher in the carcinomas compared with both fibroadenomas (P = 0.0001) and normal breast tissue (P = 0.0001). In the carcinomas, a significant relationship was found between the p52 and p54 form of Ets2 (r = 0.51, P < 0.0001; Spearman correlation). Also, in the carcinomas, a significant correlation was found between both forms of Ets2 protein and urokinase plasminogen activator (uPA) (for p52, r = 0.43, P = 0.0005, n = 68; for p54, r = 0.50, P = 0.0001, n = 68). As Ets2 binding sites are present on the uPA promoter, Ets2 may be one of the transcription factors regulating uPA expression in human breast cancer.
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PMID:Ets2 transcription factor in normal and neoplastic human breast tissue. 1638 Feb 48

Loss of E-cadherin-mediated cell-cell adhesion and expression of proteolytic enzymes characterize the transition from benign lesions to invasive, metastatic tumor, a rate-limiting step in the progression from adenoma to carcinoma in vivo. A soluble E-cadherin fragment found recently in the serum and urine of cancer patients has been shown to disrupt cell-cell adhesion and to drive cell invasion in a dominant-interfering manner. Physical disruption of cell-cell adhesion can be mimicked by the function-blocking antibody Decma. We have shown previously in MCF7 and T47D cells that urokinase-type plasminogen activator (uPA) activity is up-regulated upon disruption of E-cadherin-dependent cell-cell adhesion. We explored the underlying molecular mechanisms and found that blockage of E-cadherin by Decma elicits a signaling pathway downstream of E-cadherin that leads to Src-dependent Shc and extracellular regulated kinase (Erk) activation and results in uPAgene activation. siRNA-mediated knockdown of endogenous Src-homology collagen protein (Shc) and subsequent expression of single Shc isoforms revealed that p46(Shc) and p52(Shc) but not p66(Shc) were able to mediate Erk activation. A parallel pathway involving PI3K contributed partially to Decma-induced Erk activation. This report describes that disruption of E-cadherin-dependent cell-cell adhesion induces intracellular signaling with the potential to enhance tumorigenesis and, thus, offers new insights into the pathophysiological mechanisms of tumor development.
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PMID:Induction of uPA gene expression by the blockage of E-cadherin via Src- and Shc-dependent Erk signaling. 1722 83