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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of HER2 in estrogen receptor (ER)-positive human breast tumors has been associated with resistance to endocrine therapy. Here we investigated the effects of HER2 on expression of apoptotic pathways and modulation of tamoxifen-induced apoptosis in ER-positive MCF-7 breast cancer cells. We report that HER2 overexpression in MCF-7 cells is accompanied by up-regulation of antiapoptotic Bcl-2 and Bcl-XL proteins and suppression of tamoxifen-induced apoptosis. In addition, human tumor cell lines that are both ER positive and overexpress HER2 also express enhanced levels of Bcl-2 compared to cells that are either ER positive or overexpress HER2 alone. Our findings suggest that possible deregulation of antiapoptotic Bcl-2 and Bcl-XL may be associated with the enhanced survival of HER2-overexpressing and ER-positive breast cancer cells treated with antiestrogens.
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PMID:Overexpression of HER2 modulates bcl-2, bcl-XL, and tamoxifen-induced apoptosis in human MCF-7 breast cancer cells. 981 90

Overexpression of the HER-2 oncogene occurs in a variety of human tumors, including 25-30% of breast carcinomas, and has been associated with an adverse prognosis. Amplification of the HER-2 gene is frequently detected in tumors, but by itself may not fully account for HER-2 overexpression since transcriptional and post-transcriptional mechanisms also regulate HER-2 protein synthesis. Our studies reveal that the efficiency of HER-2 translation differs between primary and transformed cells. In primary human fibroblasts and human mammary epithelial cells, the HER-2 mRNA is associated with monosome and small polysome fractions. In contrast, in BT474 and MCF-7 human breast cancer cell lines and in COS-7 cells the mRNA co-sedimented with larger polysomes, indicating that it is more efficiently translated in these transformed cells. Northern analysis revealed no detectable mRNA size difference, and nuclease S1 protection and sequence analyses showed no differences between the HER-2 transcript leader in primary cells compared to transformed human cells. The transcript leader in all cell types contains a short upstream open reading frame that is also conserved in other mammalian species. Transient transfection assays revealed that the HER-2 transcript leader repressed downstream translation approximately five-fold in both primary and transformed cells and mutation of the upstream initiation codon alleviated most of the inhibitory effect. These results indicate that HER2 expression is translationally controlled both by a short upstream open reading frame that represses HER-2 translation in a cell type-independent manner, and by a distinct cell type-dependent mechanism that increases translational efficiency of HER-2 in transformed cells.
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PMID:Cell type-dependent and -independent control of HER-2/neu translation. 1021 54

In this study, we used a 5'-flanking region (-426/+28) of the rat prostatic probasin (rPB) gene shown to be sufficient to direct prostate-specific expression in transgenic mice in identifying the exact DNA-binding site of a putative prostate-specific transcription factor. Chloramphenicol acetyl transferase (CAT)-reporter gene analyses revealed that the construct pCAT PB -244/+52 was equally well induced by androgens in both prostatic LNCaP and nonprostatic COS-1, MCF-7, HEC-1, and HEP-1 cell lines, indicating that although the probasin gene region -244/+52 was important for androgen regulation, it was not regulated in a prostate-specific manner. Further studies suggested that the region -278/-240 was most crucial for prostate-specific expression. The sequence -426/-279 could be considered a silencer area, especially in nonprostatic cells. In deoxyribonuclease I footprinting, a protected 12-bp region was found between the nucleotides -251 and -240 only with nuclear extracts of prostatic origin. Deletion of this area decreased androgen induction significantly (P < 0.05) in transient transfections of prostatic cells compared with the wild-type reporter construct. Glucocorticoids were incapable of increasing the induction of the pCAT PB -278/+52 reporter construct compared with that of pCAT PB -244/+52 in the prostatic cell line LNCaP, suggesting that the putative prostate-specific protein acts as an inducer only when androgen and androgen receptor are present.
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PMID:Identification of the deoxyribonucleic acid-binding site of a regulatory protein involved in prostate-specific and androgen receptor-dependent gene expression. 1021 55

The mechanism of Taxol-induced apoptosis was investigated in MCF-7 human breast carcinoma cells. Taxol-induced apoptosis was associated with phosphorylation of both c-Raf-1 and Bcl-2 and activation of ERK and JNK MAP kinases. The serine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) effectively blocked apoptosis, but N-p-tosyl-L-lysine chloromethyl ketone (TLCK), another serine protease inhibitor, was without effect. TPCK treatment also prevented phosphorylation of c-Raf-1 and Bcl-2 in response to Taxol treatment. The serine protease inhibitor did not alter JNK activity, but it enhanced Taxol-induced activation of ERK1/2. Treatment of cells with the inhibitor of MEK activation, PD98059, prevented Taxol-induced ERK activation both in the presence and absence of TPCK, but did not influence survival of either Taxol- or Taxol plus TPCK-treated cells. In addition, PD98059 had no effect on c-Raf-1 or Bcl-2 phosphorylation. Thus, while the Taxol-induced phosphorylations of c-Raf-1 and Bcl-2 proteins appear to be coupled, these events can be disassociated from ERK1/2 activation. In summary, these findings suggest that phosphorylation of c-Raf-1 and Bcl-2, but not ERK1/2, are important signaling events in Taxol-induced apoptosis of MCF-7 breast cancer cells and that a TPCK inhibitable protease(s) is required for these processes.
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PMID:Serine protease inhibitor TPCK prevents Taxol-induced cell death and blocks c-Raf-1 and Bcl-2 phosphorylation in human breast carcinoma cells. 1037 21

Activation of heregulin (HRG) signaling has been implicated in the development of aggressive phenotype in breast cancer cells. The mechanisms through which HRG regulates the progression of breast cancer cells to a more invasive or motile phenotype are currently unknown. Because the process of cell migration must involve dynamic changes in the formation of new focal adhesions at the leading edge and dissolution of preexisting focal points, we explored the potential HRG regulation of paxillin, a major component of focal adhesion. Here, we report that HRG stimulation of noninvasive breast cancer MCF-7 cells resulted in the up-regulation of paxillin mRNA and protein. The observed HRG stimulation of paxillin mRNA expression was completely blocked by actinomycin D (a transcriptional inhibitor) as well as by cycloheximide (a protein synthesis inhibitor), suggesting the involvement of an inducible protein factor(s) and transcriptional regulation of paxillin mRNA by HRG. Extension of these observations to other HRG-responsive human cell lines also demonstrated that HRG has a significant capacity to up-regulate the paxillin expression. Furthermore, the levels of paxillin expression were closely linked with the coexpression of human epidermal growth factor receptor 2 (HER2)/HER3 receptors in breast cancer cell lines and in grade III human breast tumors. This study is the first demonstration of regulation of paxillin expression by a polypeptide growth factor, and it suggests a potential role for paxillin in the HER2 pathway in breast cancer.
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PMID:Transcriptional up-regulation of paxillin expression by heregulin in human breast cancer cells. 1038 44

The presence of contaminating tumor cells in autologous bone marrow or peripheral blood stem cell (PB-SC) preparations increase the likelihood of relapse in women receiving transplants for metastatic breast cancer. We describe a new technique for purging breast cancer cells (BCCs) that combines two independent strategies: (a) the specific enrichment of CD34+ progenitor stem cells by magnetic antibody cell separation (MACS), and then (b) infection of the contaminating BCCs with a recombinant adGAL-TEK marker/suicide gene adenovirus (ad-v), followed by the addition of ganciclovir (GCV). Infection with this ad-v results in three to four times greater expression of ad-v-delivered reporter gene in BCCs than in CD34+ cells. In addition -2 h, -low multiplicity of infection (50:1) adGAL-TEK infections of BCC lines (MCF-7 and BT474) eradicated >99% of BCCs after 72 h of exposure to 20 microM GCV. However, exposure to both adenovirus and GCV at the MOIs and doses used had little effect on hematopoietic stem cells to form colonies in colony-forming unit assays. adGAL-TEK infection in our model system (10(3)-10(5) BCCs added into 10(7) HSCs) also resulted in the 3 to 5 log eradication of clonogenic BCCs after the addition of GCV. MACS enrichment/purification of CD34+ cells from PB-SC contaminated with 2 x 10(6) to 5 x 10(7) BCCs followed by adGAL-TEK infection and GCV addition resulted in 5-7-log depletion of clonogenic BCCs as well as enrichment of CD34+ progenitor cells to >98%, with the recovery of >70% of hematopoietic stem cells. This adenoviral purging system is so robust that poor MACS purification, resulting in 1.5-log depletion of BCCs, still permits excellent ad-v infection and BCC killing.
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PMID:Purging of contaminating breast cancer cells from hematopoietic stem cell grafts by adenoviral GAL-TEK gene therapy and magnetic antibody cell separation. 1038 45

AKT1 (c-AKT, PKBalpha) is the cellular homolog of the protein-serine/threonine kinase oncogene, v-akt. AKT1 is activated through the insulin and platelet-derived growth factor signaling pathways in transfected fibroblasts, but little is known about the regulation of endogenous AKT1 in tumor cells. AKT1 levels were higher in a panel of human breast carcinoma cell lines than in breast epithelial cells, particularly those with higher HER2 expression. AKT1 activity was increased by either estradiol or IGF-I in estrogen-dependent MCF-7 cells, and both factors acted synergistically to increase AKT1 activity and promote cell proliferation. Stimulation of AKT1 activity by estradiol and IGF-I was blocked by the antiestrogen ICI 182780 and by the phosphatidylinositol-3-kinase inhibitor wortmannin. MCF-7 cells transfected with AKT1 exhibited partial estrogen- and IGF-I-independent growth and were more responsive to the combination of IGF-I and estradiol. AKT1-overexpressing MCF-7 cells were less sensitive to apoptosis induced by wortmannin. These findings suggest that AKT1 is a downstream effector of estrogen- and IGF-I-dependent proliferation and survival in hormone-responsive MCF-7 breast carcinoma cells.
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PMID:Role of AKT1 in 17beta-estradiol- and insulin-like growth factor I (IGF-I)-dependent proliferation and prevention of apoptosis in MCF-7 breast carcinoma cells. 1042 60

In the present studies, we demonstrate that heregulin is a potent and rapid activator of the serine/threonine kinase called Akt in the MCF-7 breast cancer cell line but not in 3 other breast cancer cell lines (T47D, HBL-100, and MDA-231). The extent of activation of Akt in the 4 cell lines correlated with the ability of heregulin to activate phosphatidylinositol 3-kinase and inhibition of the kinase blocked Akt activation. A monoclonal antibody to HER2 inhibited the ability of heregulin to activate Akt in the MCF-7 cells. BT474, a breast cancer cell line which overexpresses HER2, had high basal Akt enzymatic activity. This high basal activity was lowered when cells were pre-incubated with an anti-HER2 monoclonal antibody which is used to treat breast cancer patients. Our results indicate that heregulin is a potent activator of Akt and that overexpression of HER2 in breast cancers could also lead to activation of Akt.
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PMID:Heregulin regulation of Akt/protein kinase B in breast cancer cells. 1044 22

Several studies have shown that some organochlorine compounds act like estrogen in certain animals and in vitro cell culture systems, and therefore, there is a possibility that they could promote the process of tumorigenesis in breast cancer cells. In our previous study, two representative organochlorines, 1,1,1-trichloro 2-o-chlorophenyl-2'-p-chlorophenyl ethane (o,p'-DDT) and beta-1,2,3,4,5,6-hexachlorocyclohexane (beta HCH), were found to directly activate the protein tyrosine kinase of Neu (c-erbB-2 proto-oncogene product) immunoprecipitates isolated from MCF-7 breast cancer cells. In the current study, we also found that 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) at 1 nM and alpha-HCH isomers at 100 nM could also significantly activate protein tyrosine kinase of Neu immunoprecipitates in a cell-free system. We also found that organochlorines result in an increase of Neu protein tyrosine kinase after intact cell treatment in estrogen-depleted medium. This Neu kinase activation by beta-HCH (100 nM) was blocked when the cells were pretreated with Neu mRNA antisense oligonucleotide (p < 0.07, Student's t-test). Endogenously added alpha-, beta-, and gamma-HCH, o,p'-DDT, 2,2'-dichlorobiphenyl (2,2'-PCB), and 2,4,5-T at 100 nM were found to promote foci formation in postconfluent cultures of this cell line. This stimulatory effect caused by 17beta-estradiol, o,p'-DDT, and beta-HCH on foci formation was inhibited by coincubation with Neu monoclonal antibody (p < 0.05). Those two events induced by organochlorines (i.e., Neu kinase activation and foci formation) seemed causally correlated.
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PMID:Correlation between the activation of Neu tyrosine kinase and promotion of foci formation induced by selected organochlorine compounds in the MCF-7 model system. 1048 16

Regulation of gene transcription as a consequence of steroid receptor-DNA interaction is mediated via nuclear receptor interacting proteins (RIPs), including coactivator or corepressor proteins, which interact with both the receptor and components of the basic transcriptional unit and vary between cell types. The aim of this study was to test the hypothesis that resistance of some breast carcinomas to tamoxifen was associated with inappropriate expression of some of these RIPs. Using Northern analysis, we observed no significant difference between the amount of either TIF-1 or SUG-1 mRNA expressed in parental MCF-7 and MCF-7 tamoxifen-resistant cell lines. However, the expression of RIP140 mRNA was lower in the resistant cell line and in the presence of estradiol, the level of RIP140 mRNA was higher in the resistant cells but not in the parental cells. In a cohort of 19 tamoxifen-resistant breast tumor samples, there was no significant difference in the level of the RIP140 and TIF-1 and corepressor SMRT mRNA compared with tamoxifen-treated tumors (n = 6) or untreated tumors (n = 21). However, SUG-1 mRNA was lower in resistant breast tumors. These data provide no support for increased expression of these RIPs or decreased expression of corepressor SMRT for being a mechanism for resistance of breast tumors to tamoxifen.
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PMID:Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor interacting protein 140, and corepressor SMRT in tamoxifen-resistant breast cancer. 1058 59


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