At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

Protein kinase C is now known to be a large family of proteins, with multiple subspecies that have subtle individual enzymological characteristics. Some members of the family exhibit distinct patterns of tissue expression and intracellular localization; different kinases probably have distinct functions in the processing and modulation of a variety of physiological and pathological responses to external signals.

The molecular heterogeneity of protein kinase C and its implications for cellular regulation

The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

/pdf/specificity-and-mechanism-of-action-of-some-commonly-used-2r15uc4rwj.pdf

Specificity and mechanism of action of some commonly used protein kinase inhibitors

STATs (signal transducers and activators of transcription) are a family of latent cytoplasmic proteins that are activated to participate in gene control when cells encounter various extracellular polypeptides. Biochemical and molecular genetic explorations have defined a single tyrosine phosphorylation site and, in a dimeric partner molecule, an Src homology 2 (SH2) phosphotyrosine-binding domain, a DNA interaction domain, and a number of protein-protein interaction domains (with receptors, other transcription factors, the transcription machinery, and perhaps a tyrosine phosphatase). Mouse genetics experiments have defined crucial roles for each known mammalian STAT. The discovery of a STAT in Drosophila , and most recently in Dictyostelium discoideum , implies an ancient evolutionary origin for this dual-function set of proteins.

http://science.sciencemag.org/content/sci/277/5332/1630.full.pdf

STATs and Gene Regulation

Many gene sequences in eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured three-dimensional fold. Disordered regions can be highly conserved between species in both composition and sequence and, contrary to the traditional view that protein function equates with a stable three-dimensional structure, disordered regions are often functional, in ways that we are only beginning to discover. Many disordered segments fold on binding to their biological targets (coupled folding and binding), whereas others constitute flexible linkers that have a role in the assembly of macromolecular arrays.

Intrinsically unstructured proteins and their functions.

The Congenital Anomaly Research Center at Kyoto University's Graduate School of Medicine was established in 1975; in 2015 the center celebrated its 40th anniversary. The celebration of this anniversary included three special projects: (1) forming an achievement list, (2) preparing for a specimen exhibition, and (3) holding an anniversary symposium. This special issue of The Anatomical Record is devoting to detailing these anniversary projects. Anat Rec, 301:947-950, 2018. © 2018 Wiley Periodicals, Inc.

The 40th Anniversary of the Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine

The present invention provides a compound and a pharmaceutical composition for neuropsychological disorders or malignant tumors, the use of the compound and the pharmaceutical composition, or a method for preventing, improving, inhibiting the development of, and/or treating neuropsychological disorders or malignant tumors with the use of the compound and the pharmaceutical composition. One or more embodiments disclose a compound expressed by the following general formula (I) or (II) or a pharmaceutically acceptable salt of the compound:

Compound and pharmaceutical composition for neuropsychological disorder or malignant tumor

A composition for activating neurogenesis or the growth of neurons is provided. In one or more embodiments, a composition contains as an active ingredient a compound with a DYRK inhibitory capacity or a prodrug thereof or a pharmaceutically acceptable salt thereof. In one or more embodiments, a composition contains as an active ingredient a compound expressed by the following general formula (I) and/or (II) or prodrug thereof or a pharmaceutically acceptable salt thereof.

Compound pertaining to neuropoiesis and drug composition

Strict examinations have resulted in drastically shortened life spans for a broad range of biotech 'pioneer' patents in Japan.

Shortened life spans of biotech pioneer patents in Japan: a lesson from the DNA chip

When Castagna et al.1 demonstrated that the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) could stimulate protein kinase C activity, protein kinase C caught the attention of many scientists and has resulted in a vast and ever-growing literature on the role of protein kinase C in numerous biologic processes induced by TPA.2 Indeed, the hypothesis that protein kinase C is the one of the binding protein of the phorbol esters was attractive for cancer researchers and helped rationalize the broad range of biological activities that has been observed previously for the phorbol esters. However, could we attribute all the biological effects induced by phorbol esters to the activation of the function of protein kinase C. The gel overlay experiment using [3H]12-0-tetradecanoylphorbol-13-acetate, for example, did not give a single band of protein kinase C, suggesting that we must have more pharmacological tools for elucidating the function of protein kinase C. Therfore we have started to synthesize a specific inhibitor of protein kinase C. Since synthesizing H-7 in 1986,4 we have succeeded in utilizing the inhibitor as an affinity ligand and could purified protein kinase C reproducibly. By using this enzyme preparation, we have determined that structure of isozyme of protein kinase C and obtained monoclonal antibodies against three isozymes. We established enzyme immunoassay method and determined tissue distribution of these three isozymes.

Masatoshi Hagiwara

Papers

The 40th Anniversary of the Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine

Compound and pharmaceutical composition for neuropsychological disorder or malignant tumor

Compound pertaining to neuropoiesis and drug composition

Shortened life spans of biotech pioneer patents in Japan: a lesson from the DNA chip

Molecular pharmacology of protein kinase C.