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Spatial Distribution Of The Egf Receptor System In The Regulation Of Breast Epithelial Cell Growth And Organization
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Book Synopsis Spatial Distribution of the EGF Receptor System in the Regulation of Breast Epithelial Cell Growth and Organization by :
Download or read book Spatial Distribution of the EGF Receptor System in the Regulation of Breast Epithelial Cell Growth and Organization written by and published by . This book was released on 1998 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 184A1 cells do not form polarized, glandular epithelial structures when plated onto Matrigel, nor do they polarize if plated onto Transwell tissue culture inserts; therefore, 184A1 could not be used to address the primary aim of my proposal: to determine if the loss of receptor system polarization provides a growth advantage, enhances motility, or changes the differentiated state of normal cells. However, because the growth and motility of 184A1 cells require EGFR stimulation and because EGFR mis-regulation is implicated in the progression of human breast cancer, the 184A1 cell system still represents a excellent cell system in which to investigate EGFR regulation. My work has revealed that the constitutive endocytosis of the empty EGFR can be an active and specific form of EGFR spatial regulation in 184A1 cells. The process requires formation of coated pits, is specific and saturable for the EGFR and is upregulated at high cell densities. As a result of the rapid constitutive endocytosis, there is a significant increase in the proportion of receptors that can be found within the cell. Mounting evidence suggests that activated receptors initiate different signaling pathways if they are localized to vesicles as opposed to plasma membrane associated. Rapid constitutive endocytosis may provide a mechanism by which a large pool of receptors is made available to initate, preferentially, signals from internal vesicular membranes. Endocytosed ligands, or internalized, pre-activated E6FR or receptor family members could activate the internal pool of receptors either directly or in trans, respectively.
Book Synopsis Spatial Distribution of the EGF Receptor System in the Regulation of Breast Epithelia Cell Growth and Organization by :
Download or read book Spatial Distribution of the EGF Receptor System in the Regulation of Breast Epithelia Cell Growth and Organization written by and published by . This book was released on 1995 with total page 10 pages. Available in PDF, EPUB and Kindle. Book excerpt: 184A1 human mammary epithelial cells (HMECs) form organotypic structures when plated on Matrigel. However, the organotypic structures differentiate into squamous, not glandular, epithelia. They can not be used to examine the functional significance of a polarized epidermal growth factor receptor system in a glandular epithelia. This experimental system may be useful for investigating cell-extracellular matrix interactions that control EGF-R expression. 184A1s and subclones of the 184A1 cell line express proteins necessary for structural and functional polarization on Transwells, but do not assemble these proteins into tight junctions. MCF-7 cells express ZO-1 and assemble the protein into tight junctions when plated onto Transwells. MCF-7s also segregate B-1 integrin into the basal-lateral membrane coppartment. NCF-7 cells respond mitogenicly to EGF-R occupancy and may provide an experimental system with which to address the primary aim of my proposal: to determine if the loss of the correct spatial organization or inappropriate expression of the EGF-R system provides a growth advantage, enhances cell motility, or ochanges the differentiated state of normally organized epithelial cells.
Book Synopsis Spatial Distribution of the EGF Receptor in Regulation of Breast Epithelial Cell Growth and Organization by :
Download or read book Spatial Distribution of the EGF Receptor in Regulation of Breast Epithelial Cell Growth and Organization written by and published by . This book was released on 1995 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt: The spatial distribution of the EGF receptor and ligands is necessary for normal organization and proliferation of human mammary epithelial cells. We found that these cells express high levels of EGF receptors. These receptors are rapidly internalized and recycled. Unlike transformed cells, internalization efficiency of normal HMEC is high. These cells also make high levels of EGF, TGF-alpha, HB-EGF and amphiregulin, although TGF-alpha and amphiregulin appear to be the predominant ligands. We transfected cells with a gene encoding an artificial ligand consisting of the mature sequences of EGF (sEGF). Cells expressing sEGF could not be inhibited by antagonistic anti-EGF-R antibodies, apparently because the sEGF was working through an intracrine mechanism. Importantly, cells expressing sEGF could not organize correctly. Also, the ability of HMEC to spread and migrate on the extracellular matrix was dependent of EGF-R occupancy. Our data suggests that the ability to HMEC to spatially sense their environment is dependent on the EGF-R system through an autocrine mechanism. Importantly, these data support our hypothesis that disruptions in the spatial aspects of EGF-R signaling could facilitate the development of breast cancer.
Book Synopsis Special Distribution of the EGF Receptor System in the Regulation of Breast Epithelia Cell Growth and Organization by :
Download or read book Special Distribution of the EGF Receptor System in the Regulation of Breast Epithelia Cell Growth and Organization written by and published by . This book was released on 1996 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 184A1 human mammary epithelial cells (HMECs) form organotypic structures when plated on Matrigel; however, after three weeks on matrigel l84Al cells do not form polarized, glandular epithelial structures, nor do they polarize if plated onto Transwell tissue culture inserts. Therefore, i84Ais can not he used to address the primary aim of my proposal: to determine if the loss of the correct spatial organization or inappropriate expression of the EGF-R system provides a growth advantage, enhances motility, or changes the differentiated state of normal cells. MCF-7 cells do express a phenotype consistent with polarized epithelia when plated on Transwells, however, MCF-7 are so loosely adherent to transwells that they are refractory to typical experimental manipulation. HB2 cells are a normal, non-transformed mammary epithelial cell line that expresses high numbers of EGF-R, are tightly adherent to transwells, and polarize on transwells as determined by immunofluorescence localization of ZO-1, the EGF-R and Beta-1 integrin. HB2 may provide an experimental system with which to address the primary of my proposal. Preliminary experiments comparing 184A1s and HB2 have revealed an interesting and novel finding--rapid internalization of EGF-R can be uncoupled from the normal negative regulatory process of down-regulation.
Book Synopsis The Effects of Signaling Through the EGF Receptor System Upon Regulation of Growth in Human Mammary Epithelial Cells by : Becky Worthylake
Download or read book The Effects of Signaling Through the EGF Receptor System Upon Regulation of Growth in Human Mammary Epithelial Cells written by Becky Worthylake and published by . This book was released on 1997 with total page 17 pages. Available in PDF, EPUB and Kindle. Book excerpt: Previous reports showed that transactivation of the human epidermal growth factor receptor 2 (HER2) by epidermal growth factor (EGF) leads to the downregulation of HER2. This report presents evidence that overexpression of HER2 nearly abolished its downregulation. Unexpectedly, downregulation of the epidermal growth factor receptor (EGFR) was also inhibited by overexpression of HER2. This suggests that the EGFR and HER2 share a trafficking component which becomes limiting when HER2 is overexpressed. There are two trafficking steps which kinetic analyses predict to be regulated by a saturable component: internalization and lysosomal targeting. We show that the internalization rate of the EGFR is independent of the level of HER2 expression. Thus, we speculate that the molecule responsible for lysosomal targeting is shared between EGFR and HER2. Further, this implies that overexpression of one of the EGFR family members can cause misregulation of the receptors expressed at normal levels.
Book Synopsis The EGF Receptor Family by : Graham Carpenter
Download or read book The EGF Receptor Family written by Graham Carpenter and published by Elsevier. This book was released on 2004-02-06 with total page 175 pages. Available in PDF, EPUB and Kindle. Book excerpt: The enormity of the literature on growth factors, plus the breadth of the biological disciplines and technical expertise required prohibits a comprehensive review by even a multi-disciplinary panel of authors. To provide an alternative that is feasible for authors and digestible by readers, this review compendium consists of a collection of articles, each covering an aspect of teh ErbB/EGF field. This compilation features articles on growth factor ligands, neuregulins, and individual receptors. The second part of the book concentrates on the biological context of the ErbB receptors, particularly in mammary development and in cancer. It concludes with a discussion of the genetic systems that have enabled significant advances in research in this area.
Book Synopsis EGF Receptor in Tumor Growth and Progression by : R.B. Lichtner
Download or read book EGF Receptor in Tumor Growth and Progression written by R.B. Lichtner and published by Springer Science & Business Media. This book was released on 2013-04-17 with total page 303 pages. Available in PDF, EPUB and Kindle. Book excerpt: The last 15 years have brought an understanding of growth and differentiation at the molecular level, expanding our knowledge of the origin and progression of cancer. Early breakthroughs defining growth control pathways came via studies of oncogenes, mutated signaling molecules that have lost the capacity to tum off their proliferative signal. Oncogenes with diverse growth-promoting activities have been discovered, covering the gamut from cell surface to nuclear signaling. Sequencing of these oncogenes revealed that they were mutated forms of captured cellular genes and displayed tyrosine kinase activity. The epidermal growth factor (EGF) receptor was the first of 40-50 transmembrane tyrosine kinase receptors to be cloned and sequenced. Beyond cell proliferation, activation of EGF receptor by its specific ligands controls important physiological processes, such as cell differentiation, apoptosis, cell migration, and cell shape. Activation of autocrine growth loops, consisting in solid human tumors of upregulated expression of EGFR together with increased production of ligands suggested its crucial role in autonomous tumor growth.
Book Synopsis Estradiol and Epidermal Growth Factor Interactions in the Regulation of Mammary Epithelial Cell DNA Synthesis by : Russell John Vanderboom
Download or read book Estradiol and Epidermal Growth Factor Interactions in the Regulation of Mammary Epithelial Cell DNA Synthesis written by Russell John Vanderboom and published by . This book was released on 1993 with total page 368 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Regulated Trafficking and Spatially Restricted Signaling of the Epidermal Growth Factor Receptor in Human Mammary Epithelial Cells by : Patrick Martin Burke
Download or read book Regulated Trafficking and Spatially Restricted Signaling of the Epidermal Growth Factor Receptor in Human Mammary Epithelial Cells written by Patrick Martin Burke and published by . This book was released on 2000 with total page 364 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Mitosis-Specific Negative Regulation of EGF-Receptor in Breast Cancer: Molecular Mechanisms, Biological Significance and Therapeutic Application by :
Download or read book Mitosis-Specific Negative Regulation of EGF-Receptor in Breast Cancer: Molecular Mechanisms, Biological Significance and Therapeutic Application written by and published by . This book was released on 2000 with total page 50 pages. Available in PDF, EPUB and Kindle. Book excerpt: This project is to study the mechanisms of regulation of the EGFR during the cell cycle, in breast epithelial cells. Especially how cell which overexpress EGFR can overcome the negative regulation. We plan to use this negative regulation of the EGFR during the M phase of the cell cycle to develop a novel therapeutic strategy that uses the combination of EGF-PE and taxol as treatment. In trying to elucidate the mechanism of action of EGFR we have shown that cdc2 which can physically associate with neu, cannot associate with EGFR. Also we have shown that in vitro with treatment of EGF-PE and taxol together we do see that EGFR overexpressing cells are selectively killed, i.e. normal cells are protected from the EGF-PE by taxol treatment This novel approach may be a potential therapeutic strategy to treat breast cancer patients in the future. In addition to our proposed work we have discovered that cyclin Dl which is unregulated by EGFR can also be up regulated by beta-catenin. This work while not directly related to this proposal does help in understanding EGFR signaling pathways. Also this is a very novel finding of the correlation of the unregulation of beta-catenin and breast cancer.
Book Synopsis Regulation of ErbB Signaling in Breast Cancer Epithelial Cells by Cb1 Proto-Oncogene Product by :
Download or read book Regulation of ErbB Signaling in Breast Cancer Epithelial Cells by Cb1 Proto-Oncogene Product written by and published by . This book was released on 2002 with total page 13 pages. Available in PDF, EPUB and Kindle. Book excerpt: A large body of evidence has shown that members of the epidermal growth factor (EUF) family play critical roles in the proliferation and differentiation of normal breast epithelial cells and are important for cell proliferation in breast cancer. The response to EGF is mediated by the transmembrane receptor tyrosine ErbB 1, or epidermal growth factor receptor (EGF-R). This receptor plays a key role in the induction of proliferation in mammary epithelial cells (MECs). Overexpression of EGF-R due to gene amplification or increased transcription is seen in a third or more of all breast cancers. Receptor overexpression may be causally linked to oncogenesis, and correlates with development and progression of tumors that are refractile to standard therapeutic approaches. Thus, EGF-R is a potential target for therapeutic intervention in the subset of women with worst prognosis on conventional treatment. Understanding and manipulating the biochemical mechanisms regulating signal transduction through EGF-R therefore represent important goals in breast cancer research, and are the focus of this study. We have proposed the hypothesis that the proto-oncoprotein Cbl provides ligand-specific negative regulation of EGF-R in epithelial cells. We and others have shown that Cbl effects EGF- mediated down-regulation, ubiquitination, and degradation of EOF-R. In the 8.5 months of this reporting period (following reactivation of the award at the place of the P.I.'s independent appointment), we have tested whether Cbl's recruitment to the receptor and its ability to ubiquitinate EGF-R depends on the nature of the stimulating ligand. In vivo, EGF stimulation of EGF-R leads to receptor downregulation and the termination of signaling, but TGF-alpha stimulation of EUF-R leads to receptor recycling and prolonged signaling. We have found that EGF-activated EUF-R binds to Cbl and undergoes polyubiquitination, but TGF-alpha-activated EGF-Rdoes the same.
Book Synopsis EGFR Signaling Networks in Cancer Therapy by : John D. Haley
Download or read book EGFR Signaling Networks in Cancer Therapy written by John D. Haley and published by Springer Science & Business Media. This book was released on 2009-03-01 with total page 393 pages. Available in PDF, EPUB and Kindle. Book excerpt: The epidermal gro wth factor (EGF ) receptor and its downstream signal transduction networks have been implicated in the ontology and maintenance of tumor tissues, which has motivated the discovery and development of molecularly targeted anti-EGF receptor therapies. Over decades of study, the EGF receptor structure, its ligand binding domains, the physical biochemistry underlying its intrinsic tyrosine kinase catalytic function and the modular interactions with SH2, PTB, and SH3 domain containing signaling adaptor p- teins required for signal transduction, have been extensively dissected. Not only is the EGF receptor the nexus of many streams of information, but it also forms one part of a calcul- ing device by forming dimers and oligomers with the other three receptors in its family in response to at least eleven ligands (some of which are expressed in multiple forms with overlapping or quite distinct functions). This phenomenon, while recruiting to the inner surface of the cell membrane and activating multiple second messenger proteins, also allows the possibility of cross talk between these systems, permitting a further layer of information to be exchanged. Less well described are the cross re gulation of the EGF receptor and other anti-apoptotic, mitogenic and metabolic signaling systems. The study of these systems has yielded new surprises. One hurdle in these efforts has been that signal transduction pathways have frequently been defined in the generic absence of their tissue-specific or cell-interaction specific context.
Book Synopsis Role of Epidermal Growth Factor Receptors and Their Ligands in Normal Mammary Epithelial and Breast Cancer Cells by :
Download or read book Role of Epidermal Growth Factor Receptors and Their Ligands in Normal Mammary Epithelial and Breast Cancer Cells written by and published by . This book was released on 1997 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epidermal growth factor (EGF) and transforming growth factor a (TGFalpha) acting through EGF receptors (EGFR) regulate the development of normal mammary epithelial cells (MEC) and breast cancer. Primary culture studies examined the effects of EGF and TGFalpha in MEC. PD158780, a selective inhibitor of the tyrosine kinase domain of EGFR, helped demonstrate that EGFR signaling was required for the proliferation and functional differentiation of immature MEC from days 0-7 of culture, and survival of terminally differentiated MEC from days 17.5-21 of the study. EGFR levels were expressed at high levels in non-functional MEC and MEC undergoing apoptosis whereas functionally differentiated MEC expressed relatively low levels of EGFR. In EGF medium, cultured MEC expressed peak levels of erbB2 and erbB3 from day 7-14 of culture, whereas erbB4 levels were only detected within MEC cultured for 7 and 10.5 days. MEC isolated from mammary glands expressed high levels of erbB2 and erbB3 in virgin rats and rats during pregnancy and involution, and relatively low levels during lactation, whereas erbB4 appeared to be uniformly expressed throughout the developmental stages analyzed. These findings will help in the development of therapies to treat aggressive human breast cancers that often overexpress EGFR and/or other erbB receptors.
Book Synopsis The Role of EGF Receptor Negative Regulatory Components in Breast Cell Growth by :
Download or read book The Role of EGF Receptor Negative Regulatory Components in Breast Cell Growth written by and published by . This book was released on 1999 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Previous results showed that MDA-MB-468 cells, with 1.9 x 10(exp 6) EGF-R per cell, did not rapidly eliminate activated EGF-R. The variant cell lines S1 and S11 possessing 1.6 x 10(exp 4) and 6.6 x 10(exp 4) EGF-R per cell respectively, did rapidly eliminate activated EGF-R. S1 and S11 lines transduced with EGF-R express EGF-R levels intermediate to the S variants and the 468 cells and eliminate their activated EGF-R at an intermediate rate. We show that phosphatase activity is not limiting following receptor amplification and that all phosphotyrosine can be removed within 30 seconds. Our data suggests that PY is prolonged following receptor amplification because the amplified cell lines cannot rapidly segregate ligand and receptor during trafficking. Further, we show that receptor amplification does not increase ligand capture efficiency or increase expression of autocrine ligands. Because basal PY increases following EGF-R amplification increases in a linear fashion this data further supports our model. Lastly, basal phosphotyrosine increases following EGF-R amplification appear to be ligand dependent whereas increases in EGF-R basal PY due to Her2 amplification appear to be ligand independent.
Book Synopsis Regulation of EGF Receptor Signaling by Histone Deacetylase 6 (HDAC6)-Mediated Reversible Acetylation by :
Download or read book Regulation of EGF Receptor Signaling by Histone Deacetylase 6 (HDAC6)-Mediated Reversible Acetylation written by and published by . This book was released on 2005 with total page 39 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the hallmarks of cancer is uncontrolled cell growth and proliferation. In cells, a group of proteins called growth factor receptors are responsible for responding to the signals that trigger proliferation. When these receptors function abnormally due to genetic mutation, these can undergo uncontrolled proliferation and become cancerous. In the case of breast cancer, a specific group of growth factor receptors, the ErbB family, have been implicated in the formation of tumors. In order to prevent uncontrolled growth, normal cells tightly regulate the activity of the EGF receptors. Upon their activation, which initiates the signaling that triggers cell proliferation, the receptor is also programmed to be destroyed in order to stop growth factor-induced signaling. A defect in this destructive mechanism can result in abnormally active EGFR, which can lead to uncontrolled signaling, and thus tumor formation. Recently, it has been shown that Hsp90 (heat shock protein 90) is able to bind EGFR, and prevent its destruction. Tile ability of Hsp90 to bind substrate proteins appears to be regulated by a small chemical modification termed reversible acetylation. Hsp9O appears to require deacetylation in order to properly interact with its substrates. This would suggest that the modulation of Hsp9O acetylation status will be important for EGFR-mediated cell proliferation. Our lab has found that Hsp90 interacts with HDAC6 (histone deacetylase 6), which is a protein that acts to remove acetyl groups from proteins (deacetylation), and we hypothesize that this interaction plays a regulatory role in EGFR functioning. We aim to characterize the interaction between these proteins, and determine how this interaction effects EGFR signaling. In addition, we will examine the role of HDAC6 in EGFR-mediated breast cancer formation in a tissue culture model.
Book Synopsis The Role of the EGF Receptor First Intron in Its Regulation in Breast Canceer by :
Download or read book The Role of the EGF Receptor First Intron in Its Regulation in Breast Canceer written by and published by . This book was released on 1997 with total page 58 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hormone independent human breast cancer is characterized by estrogen receptor (ER) loss and the acquisition of high epidermal growth factor receptor (EGFR)levels. Despite the tendency for an inverse correlation between EGFR and ER, EGFR is a strong prognostic indicator for poor survival rate independent of ER status suggesting that EGFR overexpression is an important step in the progression to estrogen independence. Our studies have shown that several DNase I hypersensitive sites which correspond to potential regulatory protein binding sites reside within the EGFR gene first intron exclusively in hormone independent breast cancer cells, and micrococcal nuclease assays indicated that a disrupted and shifted nucleosome phasing pattern of the EGFR first intron occurs in a high EGFR expressing cell line. CAT assays demonstrated that a l40bp region of the first intron of EGFR has enhancer ability specifically in these hormone independent breast cancer cells. The DNA-protein interaction that occurs in this region was localized to a 35bp fragment that retains enhancer activity, and potentially to the sequence ATGACT. We hope that identifying the specific regulatory elements involved in EGFR up-regulation will assist in developing new therapies for preventing and treating aggressive, estrogen independent breast cancer.
Book Synopsis EGF Receptor in Tumor Growth and Progression by : R.B. Lichtner
Download or read book EGF Receptor in Tumor Growth and Progression written by R.B. Lichtner and published by Springer. This book was released on 1996-11-25 with total page 258 pages. Available in PDF, EPUB and Kindle. Book excerpt: The last 15 years have brought an understanding of growth and differentiation at the molecular level, expanding our knowledge of the origin and progression of cancer. Early breakthroughs defining growth control pathways came via studies of oncogenes, mutated signaling molecules that have lost the capacity to tum off their proliferative signal. Oncogenes with diverse growth-promoting activities have been discovered, covering the gamut from cell surface to nuclear signaling. Sequencing of these oncogenes revealed that they were mutated forms of captured cellular genes and displayed tyrosine kinase activity. The epidermal growth factor (EGF) receptor was the first of 40-50 transmembrane tyrosine kinase receptors to be cloned and sequenced. Beyond cell proliferation, activation of EGF receptor by its specific ligands controls important physiological processes, such as cell differentiation, apoptosis, cell migration, and cell shape. Activation of autocrine growth loops, consisting in solid human tumors of upregulated expression of EGFR together with increased production of ligands suggested its crucial role in autonomous tumor growth.
