Assessment of the Activation of Rho Family GTP-Binding Proteins in Breast Cancer Cells and Specimens PDF Download
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Author:
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ISBN:
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Languages : en
Pages : 112
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Book Description
Rho GTPases have begun to be appreciated to play roles in breast carcinogenesis. To establish a causal link between activation of individual Rho signaling events and certain aspects of breast cancer development, we have started to search for direct effect on Rho GTPases in mitogenic conditions and in various physiological situations that may be connected to mammary cell transformation. As stated in this first annual report, we have established a method using the Rho GTPase-interactive effector domains of WASP, PAK1, and Rhotekin to quantitatively define the activation-states of Rho family members Cdc42, Rac, and Rho in cells, and applied this method to four cellular conditions which are related to mammary tumorigenesis. These studies are significant since the findings further confirmed the involvement of Rho GTPases in diverse physiological situations that may contribute to oncogenesis, and have paved the way for us to examine the endogenous Rho family GTPases in mitogen-stimulated or oncogene-transformed mammary cells and in breast cancer specimens. The results obtained also strengthened our working hypothesis that certain Rho GTPases are activated in breast cancer cells and tissues and that exploration of the role Rho proteins in breast may lead to novel anti-cancer therapeutics.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 112
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Book Description
Rho GTPases have begun to be appreciated to play roles in breast carcinogenesis. To establish a causal link between activation of individual Rho signaling events and certain aspects of breast cancer development, we have started to search for direct effect on Rho GTPases in mitogenic conditions and in various physiological situations that may be connected to mammary cell transformation. As stated in this first annual report, we have established a method using the Rho GTPase-interactive effector domains of WASP, PAK1, and Rhotekin to quantitatively define the activation-states of Rho family members Cdc42, Rac, and Rho in cells, and applied this method to four cellular conditions which are related to mammary tumorigenesis. These studies are significant since the findings further confirmed the involvement of Rho GTPases in diverse physiological situations that may contribute to oncogenesis, and have paved the way for us to examine the endogenous Rho family GTPases in mitogen-stimulated or oncogene-transformed mammary cells and in breast cancer specimens. The results obtained also strengthened our working hypothesis that certain Rho GTPases are activated in breast cancer cells and tissues and that exploration of the role Rho proteins in breast may lead to novel anti-cancer therapeutics.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 116
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Book Description
Author: Kenneth van Golen
Publisher: Springer Science & Business Media
ISBN: 1441911111
Category : Medical
Languages : en
Pages : 219
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Book Description
Channing Der and colleagues provide an encyclopedic overview of the Rho GTPases, providing enough detail to make any reader well-versed in the Rho field. Finally, Sofia Merajver’s laboratory provides an overview, which details the roles of the Rho proteins in cancer progression. She provides us with the history of the study of the Rho GTPases, their regulatory and effector proteins in cancer and gives us a benchmark of where the field is today. The second section of the book details the current knowledge of the Rho regu- tory proteins in cancer progression: aberrant expression and activation of these proteins leads to dysfunctional Rho signaling and a cancer phenotype. Gary Bokoch’s laboratory has provided a detailed overview of the role of Rho guanine dissociation inhibitors (GDIs) in cancer. These molecules are involved in preventing the Rho protein from associating with the inner plasma membrane and exchanging GDP for GTP, and thus becoming active. Next, Tozu Kazasa’s labo- tory has worked on the link between heterotrimeric G proteins and Rho activation via the RGS–RhoGEFs. This aspect of Rho activation is particularly interesting in that heterotrimeric G proteins and their associated G-protein-coupled receptors are attractive and attainable therapeutic targets. Dan Billadeau’s laboratory has worked extensively on the Vav RhoGEFs, which are potent oncogenes in their own right.
Author: Marc H. Symons
Publisher: Springer Science & Business Media
ISBN: 9780306479922
Category : Science
Languages : en
Pages : 256
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Book Description
Members of the Rho family of small GTP-binding proteins (GTPases) are key signal transduction proteins that mediate signals initiated by growth factors, cytokines and cell adhesion proteins. Our knowledge about Rho GTPases has rapidly expanded over the past several years and Rho GTPases is the first book to provide a comprehensive overview of the regulation and functions of this important class of proteins. This book includes several chapters dedicated to the review of various classes of proteins that control the localization and activation state of Rho GTPases. Additional chapters discuss the wide range of biological functions that are controlled by Rho GTPases, including the organization of the actin cytoskeleton, cell proliferation and cell motility. Rho GTPases is essential reading for cell and molecular biologists, biochemists and geneticists. The critical roles of Rho family members in cancer and inflammatory diseases makes Rho GTPases also an invaluable guide for clinical investigators and pharmacologists.
Author: Edward J. Manser
Publisher: Springer Science & Business Media
ISBN: 1402034628
Category : Science
Languages : en
Pages : 307
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Book Description
Humans contain more than 20 Rho type GTPases. This volume not only presents a detailed phylogenetic analysis of Rho proteins, but also discusses the possible origins of the human members. Such an analysis of human Rho GTPases has not previously been attempted. The book includes an overview of how Rho GTPases become activated which is complemented by an extensive Chapter by Darerca Owen and Helen Mott who unravel the beautiful molecular details given to us by the many structural studies of Rho GTPases. The key areas currently being investigated in relation to these ubiquitous proteins are described for both in vitro and in vivo systems. These are presented in a format that ensures the reader can approach the topic with minimal background knowledge, while ultimately bringing the subject to the level of an expert. Timely and highly authoritative, this volume illuminates newer findings, particularly as they relate to Rho proteins in vertebrate biology.
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ISBN:
Category :
Languages : en
Pages : 0
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Book Description
We had previously shown that expression of a novel transcript that had sequence similarity to rat Rho GAP sequence was altered in breast carcinoma cell lines. We believed that the putative Rho GAP is functionally active. Rho family of proteins shares homology with the Ras super family. Our working hypothesis was that breast carcinoma where Ras mutations have not been detected could still arise from aberrant Ras signaling by virtue of loss of activity of members of Rho family or factors/proteins that affect the activity of Rho proteins. We have bacterially expressed the putative Rho GAP and shown it to have specificity toward RhoA. To further associate the biochemical activity with its well-established physiological role we have demonstrated that transfected Rho GAP can alter actin organization of fibroblast cell lines. We have transfected breast cancer cells with RhoGAP expression construct and shown it to suppress cell growth. This growth suppression pathway is mediated via p2 1. To better characterize the physiological significance of RhoGAP we have used the yeast two-hybrid system to isolate interacting proteins. The protein was shown to interact with alpha tubulin, TAX1 binding protein, SWI/SNF and HMG CoA reductase. These interactions provide a mechanism for statin induced inhibition of breast carcinoma cells and indicate as yet uncharacterized involvement of RhoGAP in other processes.
Author: Kenneth Van Golen
Publisher:
ISBN: 9781441911124
Category :
Languages : en
Pages : 230
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Book Description
Author: Ed Manser
Publisher: Springer Science & Business Media
ISBN: 1592592813
Category : Science
Languages : en
Pages : 259
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Book Description
In the last 10 years researchers have firmly established key roles for R- related GTPases in almost every aspect of cell biology. In the 1980s the pro- oncogene Ras itself was the focus of interest, though in the 1990s this shifted to the increasing variety of Ras-related proteins. In this new decade much yet needs to be done to establish the role for all the small GTPases now uncovered by the human genome project. In particular, these GTPases need to be und- stood in the appropriate biochemical and cellular contexts. In the process of trying to uncover the role of these versatile proteins, a variety of novel te- niques and methodologies has been developed. These now enable investi- tors to move easily within a diversity of fields ranging from structural studies to real-time in vivo analysis of a GTPase. In recognition of the need for access to key background methodologies, GTPase Protocols: The Ras Superfamily is devoted to techniques that are pr- ently widely used and that will continue to be the standard for researchers worldwide. Each chapter is aimed at supplying detailed methodologies to allow reproduction in any laboratory, while also providing the general pr- ciples on which the methods are based. Some of the techniques grouped in the first section apply broadly to small GTPases, whereas others in Part II are more applicable within each GTPase subfamily.
Author: Philippe Fort
Publisher: World Scientific
ISBN: 9813228806
Category : Science
Languages : en
Pages : 213
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Book Description
Rho GTPases control many aspects of cell physiology. This includes polarity, endo/exocytosis, adhesion, motility, transcriptional activation, cell cycle progression or apoptosis. In view of such pleiotropic activities, Rho-controlled signaling has proven to be of medical relevance, especially in tumorigenesis, disease-associated bone remodeling and infectiology.This book is divided into three parts. Part 1 gives an evolutionary perspective of the Rho family, its atypical members, and an overview of how Rho activity is regulated. Part 2 addresses two important aspects of multicellularity controlled by Rho-dependent pathways, namely, cell-cell interactions and mechanotransduction. It also describes how post-translational modifications control Rho activity and how this is exploited by pathogenic bacteria. Part 3 explores several examples of the variety of pathophysiological processes controlled by Rho signaling, and gives a successful example of translational research, from the inhibition of Rho activation to the development of new molecules against osteoporosis.This updated review on the biology of Rho GTPases is an essential read for molecular and cell biologists. It is also an invaluable guide to post-graduate and medical students who wish to deepen their knowledge in cell biology.
Author: Moumita Chatterjee
Publisher:
ISBN: 9781267213853
Category : Breast
Languages : en
Pages :
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Book Description
Recurrence of breast cancer is a common phenomenon and the secondary disease is usually more ravaging and fatal than the primary tumor. The molecular mechanisms underlying the cause of this potentially fatal comeback are vague still and a mystery to breast cancer researchers, thus making it a very interesting subject of research. According to the well-known metastatic cascade for primary tumors, cancer cells upon dissemination from the primary tumor site go through several steps such as invading the extracellular matrix and blood stream and surviving the immune surveillance system to finally reach a secondary site or residence. Depending on the organ microenvironment, tumor cells may either proliferate and form a successful secondary tumor, undergo apoptosis and die or remain dormant until the return of favorable conditions for growth. Several molecules including the ratio of p38MAPK/ERK ratio, integrins and others have been implicated in this process of cellular dormancy. This study is the first to look at the potential involvement of Rho GTPases in this process. The idea stemmed from previous experiments where treatment with farnesyl transferase inhibitors induced a distinct phenotype in inflammatory breast cancer cells that was consistent with the morphology of dormant cells in vitro . Since FTIs control activity of Rho GTPases, investigating the active levels of RhoA and RhoC GTPases was the next logical step. Results from this study indicate that RhoC GTPase is hyperactive in dormant breast cancer cells while RhoA GTPase is hypoactive. The cytoskeletal architecture of these cells in vitro is distinctly different with a well-spread out morphology and manipulating the active levels of these GTPases changed the state of dormancy in these low metastatic breast cancer cells. Two different models of dormancy in vitro were established, both yielding similar results. Integrin beta-1 was found to be activated in these conditions after potentially binding to fibronectin, a common extracellular matrix component in secondary metastatic sites like the bone, liver and lungs. Presence of fibroblast growth factor-2 seemed to help form focal adhesions at sites of attachment and heparan sulfate proteoglycans such as syndecan-4 probably help in this binding process. C-src was activated downstream of integrins in these cells probably through beta-tail binding proteins like talin and focal adhesion kinases that are activated in the process. Following activation, src acts as a common regulator of Rho GTPases. It helps in the complex formation between p190RhoGAP and p120RasGAP, which then translocates to the cell membrane where p190, thus activated, inactivates RhoA. Simultaneously, src activates RhoC through a potential GEF. Activation of RhoC triggers a cascade of phosphorylation of kinases such as MEKK1/4 and MKK7 finally activating c-jun NH2-terminal kinases (JNK). Activated JNK then acts upon c-jun, which translocates to the nucleus and triggers the transcription of several genes including some responsible for autophagy such as Atg 5 and Atg 12. Activation of autophagy is confirmed by expression of its marker LC3B-II. Autophagy acts as a mode of survival probably during the initial stages of dormancy to stabilize to metabolic rate to a level beneficial to the sustenance of the cell during the period of dormancy. This study provides one of many signaling pathways involved in dormancy of breast cancer. This complicated process integrates several different pathways triggered by various external and internal factors to finally induce dormancy in tumor cells, one of which is highlighted here. Also, this study outlines the behavior of dormant cells in a two-dimensional environment. Providing a three-dimensional microenvironment closely mimicking the in vivo conditions may open up numerous new possibilities involved in the complicated process of tumor dormancy in breast cancer. However, this study highlights several potential therapeutic targets to inhibit breast cancer dormancy. Use of src inhibitors like dasatinib and FTIs in conjunction with conventional chemotherapeutic regimes may eliminate the chances of recurrence thereby improving the lifespan and long-term survival rates of successfully treated breast cancer patients.
