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Author

Joseph A. Beavo

Other affiliations: Vanderbilt University, Genentech
Bio: Joseph A. Beavo is an academic researcher from University of Washington. The author has contributed to research in topics: Phosphodiesterase & Cyclic nucleotide phosphodiesterase. The author has an hindex of 73, co-authored 188 publications receiving 21097 citations. Previous affiliations of Joseph A. Beavo include Vanderbilt University & Genentech.


Papers
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Journal ArticleDOI
TL;DR: Basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed and how these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered.
Abstract: Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. The feasibility of these enzymes as drug targets is exemplified by the commercial and clinical successes of the erectile dysfunction drugs, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). PDE inhibitors are also currently available or in development for treatment of a variety of other pathological conditions. In this review the basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed. How these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered. PDEs hold great promise as drug targets and recent research advances make this an exciting time for the field of PDE research.

1,651 citations

Journal ArticleDOI
TL;DR: Some of the major concepts related to the understanding of PDE function and regulation are reviewed including the structure of catalytic and regulatory domains and arrangement in holoenzymes, the nature and function of negative and positive feedback circuits that have been conserved in PDEs from prokaryotes to human, and the emerging association of mutant PDE alleles with inherited diseases.
Abstract: Although cyclic nucleotide phosphodiesterases (PDEs) were described soon after the discovery of cAMP, their complexity and functions in signaling is only recently beginning to become fully realized. We now know that at least 100 different PDE proteins degrade cAMP and cGMP in eukaryotes. A complex PDE gene organization and a large number of PDE splicing variants serve to fine-tune cyclic nucleotide signals and contribute to specificity in signaling. Here we review some of the major concepts related to our understanding of PDE function and regulation including: (a) the structure of catalytic and regulatory domains and arrangement in holoenzymes; (b) PDE integration into signaling complexes; (c) the nature and function of negative and positive feedback circuits that have been conserved in PDEs from prokaryotes to human; (d) the emerging association of mutant PDE alleles with inherited diseases; and (e) the role of PDEs in generating subcellular signaling compartments.

1,106 citations

Journal ArticleDOI
15 Feb 2007-Nature
TL;DR: Although its function is required for Tr cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of Tr cells, including anergy and dependence on paracrine IL-2.
Abstract: Regulatory CD4+ T cells (Tr cells), the development of which is critically dependent on X-linked transcription factor Foxp3 (forkhead box P3), prevent self-destructive immune responses Despite its important role, molecular and functional features conferred by Foxp3 to Tr precursor cells remain unknown It has been suggested that Foxp3 expression is required for both survival of Tr precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and Tr suppressive capacity are intimately linked Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of Tr cells Although its function is required for Tr cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of Tr cells, including anergy and dependence on paracrine IL-2 Furthermore, Foxp3 solidifies Tr cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain Tr cells This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for Tr cell homeostasis

1,071 citations

Journal ArticleDOI
TL;DR: Much of the evidence that has led to the current understanding of multiple isozymes of phosphodiesterase is summarized, with emphasis on aspects that may be relevant to drug design.

921 citations

Journal ArticleDOI
TL;DR: Research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor–effector coupling, protein-kinase cascades and downregulation of drug responsiveness.
Abstract: Since the discovery in 1957 that cyclic AMP acts as a second messenger for the hormone adrenaline, interest in this molecule and its companion, cyclic GMP, has grown Over a period of nearly 50 years, research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades and downregulation of drug responsiveness The breadth and impact of this work is reflected by five different Nobel prizes

845 citations


Cited by
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Journal ArticleDOI
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

10,602 citations

Journal ArticleDOI
30 May 2008-Cell
TL;DR: The cellular and molecular basis of Treg development and function is revealed and dysregulation of T Regs in immunological disease is implicates.

4,427 citations

Journal Article
TL;DR: This volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of the instrument and its ancillary tools are simply and well presented.
Abstract: I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

3,197 citations

Journal ArticleDOI
TL;DR: The hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate TReg-cell function is proposed.
Abstract: Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.

2,803 citations

Journal ArticleDOI
TL;DR: Both the holoenzyme and the catalytic subunit (or fragment), which is active without an enzyme activator, are susceptible to these compounds with a similar concentration dependency, thereby indicating that the inhibitory effect is attributed to the direct interaction of the compound with the active center of the enzyme but not with the enzymeactivator.
Abstract: Naphthalenesulfonamides such as N-(6-amino-hexyl)-5-chloro-1-naphthalenesulfonamide (W-7) are potent calmodulin (CaM) antagonists and act upon several protein kinases at higher concentration. When the naphthalene ring was replaced by isoquinoline, the derivatives were no longer CaM antagonists but retained the ability to inhibit protein kinases, and some of the derivatives exhibited selective inhibition toward a certain protein kinase. cAMP-dependent, cGMP-dependent, and Ca2+-phospholipid-dependent (protein kinase C) protein kinases were inhibited significantly by addition of 10(-6) M N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H-8) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). H-8 was the most active of the inhibitors in this series and inhibited more markedly cyclic nucleotide dependent protein kinases, than other kinases, while the derivative with the sulfonylpiperazine residue (H-7) was the most potent in inhibiting protein kinase C. Apparent Ki values of H-8 were 0.48 and 1.2 microM for cGMP-dependent and cAMP-dependent protein kinases, respectively, and the Ki value of H-7 for protein kinase C was 6 microM. Both the holoenzyme and the catalytic subunit (or fragment), which is active without an enzyme activator, are susceptible to these compounds with a similar concentration dependency, thereby indicating that the inhibitory effect is attributed to the direct interaction of the compound with the active center of the enzyme but not with the enzyme activator. The inhibitions were freely reversible and of the competitive type with respect to ATP and of the noncompetitive type with respect to the phosphate acceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

2,651 citations