Mechanisms of Regulation of Protein Kinase C and Its Tumor Suppressor Function in Cancer PDF Download
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Author: Corina Elena Antal
Publisher:
ISBN: 9781321900941
Category :
Languages : en
Pages : 147
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Book Description
The serine/threonine protein kinase C (PKC) family has been extensively studied over the last 35 years, yet fundamental questions regarding the regulation of its signaling and its dysregulation in disease remain unanswered. PKC is involved in a multitude of cellular processes and precise control of the amplitude of PKC signaling is essential for maintaining cellular homeostasis. This thesis expands on the knowledge of PKC at the molecular level by unveiling how intramolecular conformational changes tune the affinity of PKC for its ligands, and at the pathophysiological level by overturning a 30-year-old scientific dogma on the role of PKC in cancer. First, mechanistic studies reveal that processing phosphorylations promote intramolecular interactions that clamp PKC in a closed conformation to prevent signaling in the absence of agonists, but allow efficient activation in response to small changes in agonist levels. These studies offer novel means of therapeutically targeting PKC with molecules or peptides that can either disrupt these interactions to activate PKC or maintain them closed to inhibit PKC activity. Second, analysis of PKC gene family mutations in human cancers reveals that they are loss-of-function, and that this loss-of-function confers a growth advantage, both in vitro and in vivo. These data suggest that therapies should focus on restoring, not inhibiting, PKC activity in the treatment of cancer. Taken together, this thesis identifies novel strategies to modulate PKC activity in therapies and, most importantly, establishes that PKC is a tumor suppressor.
Author: Corina Elena Antal
Publisher:
ISBN: 9781321900941
Category :
Languages : en
Pages : 147
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Book Description
The serine/threonine protein kinase C (PKC) family has been extensively studied over the last 35 years, yet fundamental questions regarding the regulation of its signaling and its dysregulation in disease remain unanswered. PKC is involved in a multitude of cellular processes and precise control of the amplitude of PKC signaling is essential for maintaining cellular homeostasis. This thesis expands on the knowledge of PKC at the molecular level by unveiling how intramolecular conformational changes tune the affinity of PKC for its ligands, and at the pathophysiological level by overturning a 30-year-old scientific dogma on the role of PKC in cancer. First, mechanistic studies reveal that processing phosphorylations promote intramolecular interactions that clamp PKC in a closed conformation to prevent signaling in the absence of agonists, but allow efficient activation in response to small changes in agonist levels. These studies offer novel means of therapeutically targeting PKC with molecules or peptides that can either disrupt these interactions to activate PKC or maintain them closed to inhibit PKC activity. Second, analysis of PKC gene family mutations in human cancers reveals that they are loss-of-function, and that this loss-of-function confers a growth advantage, both in vitro and in vivo. These data suggest that therapies should focus on restoring, not inhibiting, PKC activity in the treatment of cancer. Taken together, this thesis identifies novel strategies to modulate PKC activity in therapies and, most importantly, establishes that PKC is a tumor suppressor.
Author: Vivek M. Rangnekar
Publisher: Springer Nature
ISBN: 3030735729
Category : Medical
Languages : en
Pages : 328
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Book Description
Par-4 is a tumor suppressor protein first discovered and identified in 1993 by Dr. Vivek Rangnekar’s laboratory in prostate cancer cells undergoing apoptosis. Par-4 (later also known as PAWR) is a naturally occurring tumor suppressor. Studies have indicated that Par-4 selectively induces apoptosis in cancer cells while leaving normal, healthy, cells unaffected. Mechanisms contributing to the cancer-selective action of Par-4 have been associated with protein kinase A activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. Par-4 is downregulated, inactivated or mutated in diverse cancers. This first of two volumes will be the first on the market on the topic of Par-4, and will provide the opportunity for researchers to discuss the future direction of studies, broaden the scope of research, and contribute a more complete understanding of the molecule’s structural features, key functional domains, regulation and relevant basic and clinical/translational facets.
Author: Marcelo G. Kazanietz
Publisher: Springer Science & Business Media
ISBN: 1607615436
Category : Medical
Languages : en
Pages : 492
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Book Description
Protein kinase C (PKC), a family of serine-threonine kinases, rocketed to the forefront of the cancer research field in the early 1980’s with its identification as an effector of phorbol esters, natural products with tumor promoting activity. Phorbol esters had long been of interest to the cancer research field due to early studies in the mouse skin carcinogenesis model, which showed that prolonged topical application of phorbol esters promoted the formation of skin tumors on mice previously treated with mutagenic agents. Research in the last years has established key roles for PKC isozymes in the control of cell proliferation, migration, adhesion, and malignant transformation. In addition, there is a large body of evidence linking PKC to invasion and cancer cell metastasis. Moreover, it is now well established that the expression of PKC isozymes is altered in various types of cancers. More importantly, small molecule inhibitors have been developed with significant anti-cancer activity. The relevance of PKC isozymes in cancer signaling is therefore remarkable. This book will have 4 sections. There will be 23 chapters. Each section will have a brief introduction by an expert in the field (~ 1-2 pages).
Author: Timothy R. Baffi
Publisher:
ISBN:
Category :
Languages : en
Pages : 212
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Book Description
Protein kinase C (PKC) isozymes transduce the myriad of signals downstream of phospholipid hydrolysis that potentiate an array of cellular processes including proliferation, differentiation, migration, and memory. PKC function is dysregulated in a variety of pathological states, including cancer and neurodegenerative disease. To maintain signaling fidelity, PKCs rely upon precise regulatory mechanisms that orchestrate the phosphorylations and conformational transitions that specify their signaling output. This thesis describes the molecular mechanisms by which PKC phosphorylation and autoinhibition depends upon the kinases PDK1 and mTORC2, and is opposed by PHLPP phosphatases, to produce a primed enzyme that is appropriately tuned to respond to activating signals. Specifically, we uncover the molecular basis for the controversial role of mTORC2 in AGC kinase activation by identifying a novel and conserved mTOR phosphorylation site in the C-terminal tail. Phosphorylation of this, which we term the TOR-Interaction Motif (TIM), promotes PDK1 phosphorylation of the activation loop and intramolecular autophosphorylation of the hydrophobic motif to control activation of PKC and related AGC kianse Akt. Examination of the interrelated processes of phosphorylation and autoinhibition unveils a critical role for the pseudosubstrate in protecting PKC from dephosphorylation by phosphatase PHLPP1, which selectively promotes the dephosphorylation and degradation of aberrantly active PKCs to provide a PKC quality control mechanism. High-throughput protein-level analysis from patient samples reveals that PKC quality control is a critical signaling node that sets PKC expression levels and serves as a prominent loss-of-function mechanism to impair PKC tumor-suppressive function in cancer. Critically, diseases driven by PKC dysregulation rely upon impaired PKC quality control. LOF PKC mutations in chordoid glioma act in a dominant-negative fashion to globally suppress PKC output; whereas, GOF PKC mutations in spinocerebellar ataxia drive phosphoproteome-wide changes in the cerebellum. Taken together, this thesis expands upon biochemical mechanisms of PKC maturation to identify the structural and molecular determinants of PKC phosphorylation and implicates PHLPP1 as the master regulator of PKC signaling fidelity through PKC quality control. This work is not only relevant to the pathology of disease-associated mutations in cancer and neurodegenerative disease, but also to the development of therapeutics that attempt to modulate PKC activity by targeting these regulatory mechanisms.
Author: Robert C. Bast, Jr.
Publisher: John Wiley & Sons
ISBN: 111900084X
Category : Medical
Languages : en
Pages : 2004
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Book Description
Holland-Frei Cancer Medicine, Ninth Edition, offers a balanced view of the most current knowledge of cancer science and clinical oncology practice. This all-new edition is the consummate reference source for medical oncologists, radiation oncologists, internists, surgical oncologists, and others who treat cancer patients. A translational perspective throughout, integrating cancer biology with cancer management providing an in depth understanding of the disease An emphasis on multidisciplinary, research-driven patient care to improve outcomes and optimal use of all appropriate therapies Cutting-edge coverage of personalized cancer care, including molecular diagnostics and therapeutics Concise, readable, clinically relevant text with algorithms, guidelines and insight into the use of both conventional and novel drugs Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates
Author: An-Angela Ngoc Van
Publisher:
ISBN:
Category :
Languages : en
Pages : 152
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Book Description
Protein kinase C (PKC) plays a critical role in cell signaling and homeostasis, regulating biological processes such as proliferation, differentiation, and apoptosis. Its dysregulation is associated with a multitude of pathophysiological states, with recent analyses of disease-associated mutations indicating that loss of PKC function is generally associated with cancer and gain of function with degenerative diseases. This dissertation expands on the mechanisms of PKC dysregulation in cancer, focusing on how gene fusions or mutations that disrupt autoinhibition cause loss of PKC. In the first part of the dissertation, newly identified PKC gene fusions in cancer encoding proteins that retain either the PKC catalytic or regulatory domain were characterized. Overexpression of catalytic domain fusions in cells revealed that they are constitutively active, as assessed using biosensors and other cellular assays. However, their inability to adopt an autoinhibited conformation resulted in their marked stability compared to full-length PKC. To assess whether these fusions were too unstable to accumulate at endogenous levels, CRISPR/Cas9-mediated gene editing was used to engineer a fusion of TANC2 with PRKCA. While the fusion mRNA was detected in the engineered cells, no detectable protein was expressed. Thus, the catalytic domain fusions are paradoxically loss-of-function. Characterization of a regulatory domain fusion revealed a dominant-negative role for the protein, suppressing the activity of wild-type PKC. The second part of the dissertation focused on additional mechanisms by which PKC is dysregulated in cancer. This work showed that [1] PKC that cannot be autoinhibited is subject to dephosphorylation by the phosphatase PHLPP and unphosphorylated PKC is sensitive to degradation; [2] inactivating mutants of PKC can be dominant-negative by sequestering common titratable components; and [3] impairment of the regulatory domains causes mislocalization of PKC. Taken together, these studies illustrate the diverse ways in which PKC function is lost in cancer, allowing cancer cells to overcome this cellular brake to tumor growth.
Author: Dean J. Pierce
Publisher:
ISBN: 9781536132106
Category : Protein kinase C
Languages : en
Pages : 0
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Book Description
In this compilation, the authors review the structural basis of PKC isozymes and focus on the C1 domain, as well as the plausible binding mechanisms of its activators. Additionally, the recent molecular dynamics simulation studies of how phorbol esters or bryostatin bind to the activator pocket are described and some of the key amino acid residues recently identified as important for activator binding are investigated. The following chapter focuses on the expression pattern and function of PKCα in cancer cells, and newly emerging PKCα-targeted cancer therapies. PKCα acts directly and/or indirectly in various signaling mechanisms in cancer cells, including proliferation, survival, invasion, migration, apoptosis and drug resistance. A final review is provided which dissects the crosstalk between p53 and PKCδ in the context of apoptotic cell death and cancer therapy. PKCδ is implicated in a transcriptional regulation of the p53 tumor suppressor that is critical for cell cycle arrest and apoptosis in response to DNA damage.
Author: Armen Parsyan
Publisher: Springer
ISBN: 9401790787
Category : Medical
Languages : en
Pages : 709
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Book Description
This book, for the first time, comprehensively assembles and analyzes a large body of information on the role of the fundamental mechanism of the protein biosynthesis pathway, translation, in cancer biology. It systematically explores the function of the translation machinery and its regulation, including cell signaling, in the development, maintenance and progression of human cancer. The work presented here unveils the tremendous potential and applications of this vast and exciting branch of genetic, biochemical and molecular science in cancer medicine and drug development. Chapters contributed by experts in the field take the reader on a journey that starts with a dissection of the translation machinery and its regulation in norm and cancer. Later chapters characterize etiological and pathogenetic roles that translation plays in specific cancer types. Various aspects of diagnostic, prognostic and therapeutic significance of the translation machinery and its control in cancer are discussed. Readers will discover the importance of the process of translation and its regulatory mechanisms in physiology and cancer biology. The chapters and the numerous illustrations included here were contributed by expert scientists and clinicians from renowned academic and clinical establishments in Canada, the United States of America, the United Kingdom, Italy, France, Belgium, Spain, Germany and Australia. The book conveys information and knowledge that may interest a broad range of students and scholars ranging from basic scientists to clinicians and drug developers seeking to better understand the protein synthesis and its aberrations in cancer biology and cancer medicine.
Author: Marcelo G. Kazanietz
Publisher: Humana Press
ISBN: 9781607615453
Category : Medical
Languages : en
Pages : 494
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Book Description
Protein kinase C (PKC), a family of serine-threonine kinases, rocketed to the forefront of the cancer research field in the early 1980’s with its identification as an effector of phorbol esters, natural products with tumor promoting activity. Phorbol esters had long been of interest to the cancer research field due to early studies in the mouse skin carcinogenesis model, which showed that prolonged topical application of phorbol esters promoted the formation of skin tumors on mice previously treated with mutagenic agents. Research in the last years has established key roles for PKC isozymes in the control of cell proliferation, migration, adhesion, and malignant transformation. In addition, there is a large body of evidence linking PKC to invasion and cancer cell metastasis. Moreover, it is now well established that the expression of PKC isozymes is altered in various types of cancers. More importantly, small molecule inhibitors have been developed with significant anti-cancer activity. The relevance of PKC isozymes in cancer signaling is therefore remarkable. This book will have 4 sections. There will be 23 chapters. Each section will have a brief introduction by an expert in the field (~ 1-2 pages).
Author: Bruce Alberts
Publisher:
ISBN: 9780815332183
Category : Cytology
Languages : en
Pages : 0
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Book Description
