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Author: Robert Shiu
Publisher:
ISBN:
Category :
Languages : en
Pages : 43
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Book Description
Proprotein convertases are members of a new class of endoproteolytic enzymes that are believed to play important roles in human neoplasia. Based on our previous detection of proprotein convertases in human breast tumors, the present study is designed to study the biological significance of these enzymes in breast cancer. Proprotein convertase gene transfections into MCF-7 human breast cancer cells led to profound changes in the breast cancer cells. MCF-7 cells that over-expressed proprotein convertases have become more dependent on estrogen for growth both in vitro and in vivo as tumors grown in athymic mice. As well, convertase-transfected breast cancer cells become more resistant to the anti-estrogen Tamoxifen. To further study the role of proprotein convertases in mammary gland development and tumorigenesis, transgenic mice bearing a convertase transgene targeted to the mammary gland have been generated. Characterization of these novel transgenic mice with respect to breast development and tumorigenesis is in progress.
Author: Robert Shiu
Publisher:
ISBN:
Category :
Languages : en
Pages : 43
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Book Description
Proprotein convertases are members of a new class of endoproteolytic enzymes that are believed to play important roles in human neoplasia. Based on our previous detection of proprotein convertases in human breast tumors, the present study is designed to study the biological significance of these enzymes in breast cancer. Proprotein convertase gene transfections into MCF-7 human breast cancer cells led to profound changes in the breast cancer cells. MCF-7 cells that over-expressed proprotein convertases have become more dependent on estrogen for growth both in vitro and in vivo as tumors grown in athymic mice. As well, convertase-transfected breast cancer cells become more resistant to the anti-estrogen Tamoxifen. To further study the role of proprotein convertases in mammary gland development and tumorigenesis, transgenic mice bearing a convertase transgene targeted to the mammary gland have been generated. Characterization of these novel transgenic mice with respect to breast development and tumorigenesis is in progress.
Author:
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Category :
Languages : en
Pages :
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Proprotein convertases have been proposed to be critical enzymes important in the progression of breast cancer, based on their unique property of generating biologically active growth and receptor molecules from their inactive precursors. In order to understand the biological action of proprotein convertases in the human breast cancer cell line, MCF-7 was stably transfected with a CMV-mPC1/neo construct. Eight G418 resistant clones were tested by northern blot and Southern blot; only clone 2 and clone 6 were found to express mPC1 mRNA. Clone 6, as a higher expressor of mPC1 mRNA level compared to clone 2, was labeled with $\sp{35}$S-Cysteine. Twenty-four hours after labeling, both cell lysate and medium were collected. Immunoprecipitation with rabbit polyclonal anti-PC1 antibody followed by one- and two-dimensional SDS-polyacrylamide gel electrophoresis was carried out, to confirm that an elevated level of mPC1 protein was produced in the stable transfected cell line. In order to identify potential PC1 target proteins in human breast cancer, two-dimensional gel analysis was used to compare cellular proteins between clone 6 and clone 7; the latter was a G418 resistant clone but did not contain an integrated mPC1 construct. After four separate experiments, four consistent and reproducible proteins were identified which differed between clone 7 and clone 6. One or more of these proteins may be a candidate for PC1 cleavage in human breast cancer. Further analysis of these protein spots is necessary to gain insights into the identity and potential relationship between these proteins.
Author: Nanlan Xu
Publisher:
ISBN:
Category :
Languages : en
Pages : 224
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Author: Abdel-Majid Khatib
Publisher: Biota Publishing
ISBN: 1615045376
Category : Science
Languages : en
Pages : 88
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Book Description
Proprotein convertases (PCs) are a family of proteases including PC1, PC2, Furin, PC4, PACE4, PC5, and PC7. These enzymes are involved in the maturation of many precursor proteins involved in the process of tumorigenesis and metastasis. Since their discovery, PCs were suggested as potential targets for anti-cancer therapy, and their activity was found to directly affect tumor cell proliferation, migration invasion, and the malignant phenotypes of tumor cells. Here, we discuss a number of previous and recent findings on the PCs features, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells, and their clinical relevance in cancer patients. Among the substrates of the proprotein convertases, various growth factors, their receptors, adhesion molecules, and proteases were identified. The PCs are inhibited by endogenous and exogenous inhibitors. To date, only pro7B2, a specific chaperone of PC2, and the granine-like precursor of neuroendocrine protein proSAAS, a selective ligand of PC1, have been identified as endogenous inhibitors of the PCs found in the regulated pathway. However, only PCs prosegments, several bioengineered inhibitors, peptides, and non-peptide compounds were found to inhibit the activity of the PCs found in the secretory pathway.
Author: Daniel Bassi
Publisher: Morgan & Claypool Publishers
ISBN: 1615044647
Category : Cancer
Languages : en
Pages : 51
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Book Description
Gynecological cancers include neoplasias of internal female genital organs, mainly ovarian, endometrial and cervical tumors, and cancers of the external female genital structures. Current scientific evidence indicates that both up- and down-regulation of the expression of PCs are part of the multiple changes occurring in these gynecological tumors. Nevertheless, the physiological significance of this puzzling pattern of PC expression remains elusive. The fact that PCs can activate both pro- and anticarcinogenic substrates may indicate that the nature of the overexpressed substrates in certain cancer types could determine the final outcome; i.e., slowing or accelerating cancer development.
Author: Xiaowei Sun
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"Cancer is a leading cause of death worldwide and accounts for about one fifth of all death in the Western world. In 2008, nearly 12.7 million new cancer cases and 7.6 million cancer deaths occurred worldwide. The development of cancer is a multistage process, during which cells acquire a series of mutations that eventually lead to unrestrained cell growth, evasion of cell death, angiogenesis, invasion of the surrounding tissue and finally spreading to other parts of the body. The mammalian proprotein convertases (PCs) constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. They have been associated with cancer since the early 1990s. By processing cancer-associated factors, PCs are believed to play key roles in almost every step of cancer development. Seven of these PCs (PC1, PC2, furin, PC4, PC5/6, PACE4 and PC7) activate, or less frequently inactivate, a wide variety of substrates, including hormones, growth factors, receptors, adhesion molecules, angiogenic factors, metalloproteases. Among these substrates, some of them are key factors controlling cancer progression and metastasis. The last member of this family proprotein convertase subtilisin kexin 9 (PCSK9) only cleaves itself and participates in maintaining the levels of cholesterol, which was shown to have impacts on cancer incidence.In this thesis, I focused on the role of two PCs, PC5/6 and PCSK9, in cancer development. I first showed that PC5/6 is systematically down-regulated in human and mice intestinal tumors. In ApcMin/+ mice which are a colonic cancer model and develop numerous adenocarcinomas along the intestinal tract, the specific knockout of PC5/6 in the intestine and colon leads to higher number of tumors, particularly in duodenum. This suggests that PC5/6 plays a protective role against tumorigenesis in the intestine. Although PC5/6 is protective in intestinal cancer, it has been shown to promote tumor progression in other cancer types e.g., brain and skin. Interestingly, PC5/6 is inhibited by some natural inhibitors, the latent TGFbeta binding proteins 2 and 3 (LTBP-2, -3). These two proteins reduce the enzymatic activity of PC5/6A and reduce the bio-availability of PC5/6A by sequestering the zymogen proPC5/6 in the extracellular matrix. Finally, I demonstrated that the lack of PCSK9 leads to a significantly lower level of liver metastasis of melanoma cells. This cancer protective effect is due to low plasma cholesterol levels as well as high apoptosis in liver stroma and metastasized tumors that are associated with PCSK9 deficiency.In summary, the present cumulative data define some of the in vivo roles of PC5/6 and PCSK9 in cancer and should enhance our appreciation of the physiological impact of PC inhibition." --
Author: Peter Merakos
Publisher: Morgan & Claypool
ISBN: 9781615044863
Category : Medical
Languages : en
Pages :
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Author: Abdel-Majid Khatib
Publisher: Springer Science & Business Media
ISBN: 1402051328
Category : Medical
Languages : en
Pages : 161
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Book Description
Convertases are widely expressed activating enzymes involved in various physiological and pathological processes. This book provides detailed and updated information on the role of these molecules in cancer. It is the first to summarize current knowledge of the importance of protein precursors maturation by the convertases in tumor progression, angiogenesis and metastasis. Each chapter discusses the importance of the convertases in the activation of various cancer-related molecules including growth factors, adhesion molecules and proteases.
Author: Utpal Chandra De
Publisher: Biota Publishing
ISBN: 1615044752
Category : Science
Languages : en
Pages : 78
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Book Description
The Ca+2-dependent mammalian Proprotein Convertase Subtilisin Kexins (PCSKs) or Proprotein/ Prohormone Convertases (PCs) are a family of endoproteases that play critical roles not only in normal development and metabolism but also in various physiological and pathological conditions. These were initiated by the proteolytic processing of large inactive proproteins into their shorter bioactive mature forms by the PCSK enzymes. These events take place in a highly selective, orchestrated, and stepwise manner. Among the various proprotein substrates of PCSK enzymes, particularly important are the precursor growth factors that include proPDGF-A, B, proIGF-1, 2 and proVEGF-C because of their strong implications in neoplasia initiation, progression, and metastasis. As a result of these findings, PCSK enzymes, particularly furin or PCSK3, became a major target for possible interventions of cancer via the use of their selective inhibitors. Significant progress has been accomplished in the development of peptide and protein-based PCSK inhibitors. However, non-peptide PCSK9 inhibitors are more preferable because of their drug-like and other characteristics. So far, a few non-peptide inhibitors of PCSK enzymes of various types of chemical structures have been described in the literature. These include (i) Carbocyclic compounds of diterpene and streptamine class. (ii) Nitrogen (N)-based heterocyclic compounds of various types and chemical structures such as (a) pyrrolidine bis piperazines, (b) Cu/Zn chelating terpyridine derivatives; (iii) Oxygen (O)-based Heterocyclic compounds of varying types of chemical structures such as (a) Flavonoids, (b) Coumarins of simple and dimeric types, (c) Quinonoids, (d) Iridoids; (iv) Aromatic compounds such as (a) Aryl guanidino and amidino derivatives, (b) Naphthyl fluorescein derivative, and (c) Phenyl Arsonic acids; and (v) C2-symmetrical aromatic azo-compounds. When measured against a small peptidyl-MCA fluorogenic substrate, these inhibitors displayed IC50 values ranging from nM to μM. A number of these inhibitors exhibited significant anti-PCSK activity when tested in ex vivo or cell culture conditions. This article provides an overall review of all non-peptide PCSK inhibitors so far reported in the literature along with those we identified recently for the first time and not yet published. The potential implications of these molecules as biochemical, therapeutical, or clinical agents will also be discussed.
Author: Alan J. Barrett
Publisher: Academic Press
ISBN: 0123822203
Category : Science
Languages : en
Pages : 4097
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Book Description
Extensively revised and updated, the new edition of the highly regarded Handbook of Proteolytic Enzymes is an essential reference for biochemists, biotechnologists and molecular biologists. Edited by world-renowned experts in the field, this comprehensive work provides detailed information on all known proteolytic enzymes to date. This two-volume set unveils new developments on proteolytic enzymes which are being investigatedin pharmaceutical research for such diseases as HIV, Hepatitis C, and the common cold. Volume I covers aspartic and metallo petidases while Volume II examines peptidases of cysteine, serine, threonine and unknown catalytic type. A CD-ROM accompanies the book containing fully searchable text, specialised scissile bond searches, 3-D color structures and much more. The only comprehensive book on proteolytic enzymes Includes 671 chapters, each written by experts in their field, on proteolytic enzymes from all groups of living organisms and the viruses, including those that are currently major targets of pharmaceutical research Accompanying CD-ROM provides fully searchable text, 2D structures of peptidases in color and links directly to PubMed and MEROPS databases Each chapter describes in detail the enzyme name, its history, activity and specificity, structural chemistry, preparation, biological aspects and distinguishing features Over 1000 peptidases included
