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      Local cAMP signaling in disease at a glance

      Author(s): 1 , 2 , 3
      Publication date Created:
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      Journal: Journal of Cell Science
      Publisher: The Company of Biologists

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          Summary

          The second messenger cyclic AMP (cAMP) operates in discrete subcellular regions within which proteins that synthesize, break down or respond to the second messenger are precisely organized. A burgeoning knowledge of compartmentalized cAMP signaling is revealing how the local control of signaling enzyme activity impacts upon disease. The aim of this Cell Science at a Glance article and the accompanying poster is to highlight how misregulation of local cyclic AMP signaling can have pathophysiological consequences. We first introduce the core molecular machinery for cAMP signaling, which includes the cAMP-dependent protein kinase (PKA), and then consider the role of A-kinase anchoring proteins (AKAPs) in coordinating different cAMP-responsive proteins. The latter sections illustrate the emerging role of local cAMP signaling in four disease areas: cataracts, cancer, diabetes and cardiovascular diseases.

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          Hallmarks of Cancer: The Next Generation

          Douglas Hanahan, Robert A. Weinberg (2011)
          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 11623 times – based on 0 reviews     Review now
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            Mutations of the BRAF gene in human cancer.

            Helen Davies, Graham Bignell, Charles Cox … (2002)
            Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
            Article 0 comments Cited 843 times – based on 0 reviews     Review now
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              Selective inhibition of BET bromodomains

              Panagis Filippakopoulos, Jun Qi, Sarah Picaud … (2010)
              Epigenetic proteins are intently pursued targets in ligand discovery. To date, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic “writers” and “erasers”. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) which binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity toward a subset of human bromodomains is explained by co-crystal structures with BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific anti-proliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof of concept for targeting protein-protein interactions of epigenetic “readers” and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
              Article 0 comments Cited 615 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: Journal of Cell Science
                Publisher: The Company of Biologists
                ISSN (Electronic): 1477-9137
                ISSN (Print): 0021-9533
                Publication date Created: October 15 2013
                Publication date (Print): October 15 2013
                Volume: 126
                Issue: 20
                Pages: 4537-4543
                Affiliations
                [1 ]Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
                [2 ]Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
                [3 ]Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, 1959 Pacific Avenue NE, Seattle, WA 98195, USA
                Article
                DOI: 10.1242/jcs.133751
                PMC ID: 3795333
                PubMed ID: 24124191
                SO-VID: 194302ca-ee90-4214-8c37-031526a81a21
                Copyright © © 2013
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