DOCSLIB.ORG

Protein Kinase C As Atherapeutictarget Beverlya

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Protein Kinase C As Atherapeutictarget Beverlya Review Protein Kinase C as aTherapeuticTarget BeverlyA. Teicher The recognition of protein kinase C (PKC) as the long sought- from intracellular stimuli to biological responses. Many after receptor for the tumor-promoting phorbol esters estab- proteins have been identified as PKC substrates both in vitro lished the potential role of PKC in carcinogenesis and as a and in vivo.Interestingly,however,knowledgeofPKC potentially important target for cancer therapeutics (1, 2). PKC substrates is not currently matched by the detailed understand- is a family of serine/threonine kinases that regulate a variety of ing of PKC regulation (2–4, 6). PKC isoforms are widely cell functions including proliferation, gene expression, cell distributed in tissues, although some isoforms are selectively cycle, differentiation, cytoskeletal organization cell migration, expressed. PKCg is selectively expressed in the central nervous and apoptosis (3). The PKC family was the first recognized system and spinal cord, PKCu is expressed by skeletal muscle receptor of diacylglycerol. Aberrant PKC activation can lead to and hematopoietic cells, and PKCh is expressed in pancreatic diseases of cellular dysregulation such as cancer and diabetes. islet cells, monocytes, brain, and retinal tissue (2). The existence of multiple isozymes of PKC raised the question Many kinases display overlapping substrate specificities of whether each PKC isozyme has a specific function. The PKC in vitro and can functionally compensate for each other in family includes isozymes [a, hI, hII, g, y, q, u, D, E/L (mouse/ single-gene knockout experiments. Early investigations regard- human), and ~] which are involved in signal transduction from ing the role of PKC isoforms in various intracellular signaling membrane receptors to the nucleus (Fig. 1; ref. 4). Differences events were based on a linear paradigm (6). Recent studies in PKC isozyme protein structure and substrate preferences show that signaling molecules aggregate to form multiprotein have allowed the family to be divided into three groups (2). complexes, a phenomenon that seems to hold a number of First, the conventional PKC isozymes (a, hI, hII, and g) are various types of molecules in close proximity. The formation of calcium-dependent and are phospholipid- and diacylglycerol- these complexes may facilitate signal transduction and allow activated kinases. Second, the novel isozymes (y, q, A, and u) are the modulation of biological functions within the cell. PKC calcium-insensitive, phospholipid-dependent, and diacylgly- isozymes do not function in isolation but exist in complexes cerol-dependent. Third, the atypical PKC isozymes (D and E/L) with other signaling molecules. are both calcium- and diacylglycerol-insensitive enzymes. The PKChI, PKCq, and PKCg are targets in phorbol ester– activation mechanism of the PKC isozyme family is clearly mediated tumor promotion/progression, whereas PKCy is different among the three subgroups: conventional, novel, and tumor-suppressive (Fig. 1). Disulfide forms of thiols have atypical PKC, but whether or not each isozyme in a subgroup oxidative regulatory effects on PKC isozymes and PKC S- has a specific function or activation mechanism has not been thiolation by disulfiram induces differential regulatory effects clarified. The activation and degradation of the PKC isozymes is on PKC isozymes that correlate with the cancer-preventive y controlled spatially and temporally (5). PKC is a single activity of disulfiram (7, 8). Overexpression of PKC stimulates polypeptide with four conserved regions and four variable apoptosis in a wide variety of cell types through a mechanism that is incompletely understood (9). PKCy-deficient cells are regions having a COOH-terminal catalytic domain and a NH2- terminal regulatory domain (2). The multiple functions of PKC impaired in their response to DNA damage–induced apoptosis, y in signal transduction are regulated by targeting PKC to specific suggesting that PKC is required for an apoptotic response to intracellular compartments. Several PKC isozymes may be stress. Using adenoviral vectors, Santiago-Walker et al. (9) y q capable of phosphorylating the same substrate. The constitu- found a modest increase in PKC activity but PKCa or PKC tive, lipid-dependent protein kinase activity of purified PKC activity was not able to selectively stimulate quiescent cells to y delayed the realization that PKC phosphorylation plays a initiate G(1) phase cell cycle progression. The PKC -infected fundamental role in their catalytic activities. PKC phosphory- cells arrest in S phase and proceed to caspase-dependent lation in vivo is well documented and is important in the apoptotic cell death. Further delineating the PKC isozymes, L maturation of the enzyme to a fully functional form localized Gustafson et al. (10) showed that atypical PKC is required for correctly in the cell. Bcr-Abl-mediated resistance of human K562 chronic myeloge- The identification of physiologically relevant substrates of the nous leukemia cells to paclitaxel-induced apoptosis. When Bcr- 11 known PKC isozymes is of obvious importance for a Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic h h L complete understanding of the mechanisms by which this leukemia cells, the expression of PKC I, PKC II, and PKC y family of serine/threonine protein kinases relays information was induced whereas expression of PKC was decreased. Thus, Bcr-Abl-mediated transformation involves transcriptional acti- vation of the PKCL gene leading to Bcr-Abl-mediated chemo- resistance. Author’s Affiliation: Genzyme Corporation, Framingham, Massachusetts Understanding the mechanisms by which PKC contribute to Received 4/18/06; revised 6/29/06; accepted 7/7/06. malignancy remains a challenge (11). One model critically Requests for reprints: Beverly A. Teicher, Genzyme Corporation, 5 Mountain implicates conventional PKChII (diacylglycerol-responsive) Road, Framingham, MA 01701-9322. Phone: 508-271-2843; Fax: 508-620- and atypical PKCE/L (diacylglycerol-unresponsive) in cancer 1203; E-mail: [email protected]. F 2006 American Association for Cancer Research. cell transformation and invasion. PKCE/L is markedly up- doi:10.1158/1078-0432.CCR-06-0945 regulated in human colon and lung tumors, in an in vivo model Clin Cancer Res 2006;12(18) September 15, 2006 5336 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2006 American Association for Cancer Research. Targeting PKC in CancerTherapy Fig. 1. Schematic of placement of PKC isoforms in intracellular signaling pathways. of chemically induced colon carcinogenesis, and in the survival of keratinocytes exposed to UV radiation (14). expression of activated PKCE/L-promoted hypersensitivity of Recently, Aziz et al. (15) showed that PKCy overexpression in mice to a carcinogen. transgenic mice failed to suppress the induction of squamous cell carcinoma developed by repeated exposure to UV radiation. Skin Cancer Transgenic mice that overexpress PKCq protein in basal epidermal cells and cells of the hair follicle develop papilloma- The PKC family is important in normal keratinocyte biology independent metastatic squamous cell carcinoma elicited by and in skin diseases, especially skin cancer (12). Keratinocyte 7,12-dimethylbenz(a)anthracene-initiation and 12-O-tetra- apoptosis induced by UV radiation is a major protective decanoylphorbol-13-acetate promotion. Chronic exposure of mechanism from photocarcinogenesis. The constitutively active PKCq transgenic mice to UV radiation indicates that PKCq catalytic domain of PKCy is an apoptotic effector generated by signals tumor necrosis factor-a release, which is linked to caspase-3 cleavage of full-length PKCy in response to a wide photosensitivity in these mice (16). The overexpression of variety of apoptotic stimuli including UV radiation (13). The PKCq in the epidermis of mice may lead to the induction of activated PKCy catalytic domain triggers the redistribution and specific cytokines that perturb normal hematopoiesis in activation of Bax that can directly induce cytochrome c release. bone marrow, resulting in a granulocytic skew toward neu- PKCy also activates upstream components of the death effector trophils and eosinophils (17, 18). Both the transgenic pathway to insure apoptosis. The cleavage and activation of overexpression of PKCq in mouse epidermis and human PKCy are critical components of UV-induced apoptosis in squamous cell carcinoma indicate that high expression of human keratinocytes. Inactivation of PKCy can promote the PKCq in the epidermis may lead to a microenvironment www.aacrjournals.org 5337 Clin Cancer Res 2006;12(18) September 15, 2006 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2006 American Association for Cancer Research. Review suitable for the development of squamous cell carcinoma by a carcinogenesis. Transgenic expression of PKChII in mouse colon paracrine mechanism. led to hyperproliferation and increased susceptibility to colon carcinogenesis that correlated with decreased expression of Colon and Gastric Cancer transforming growth factor-h type II receptor. Yu et al. (20) showed that transfection with PKChII induced the expression of PKC activity is higher in actively proliferating colonic cyclooxygenase-2 in rat intestinal epithelial cells in culture and epithelial cells than in their quiescent counterparts, suggesting in transgenic PKChII mice. Transgenic mice expressing PKChII a role for PKC in proliferation. Colonic
Load more

Recommended publications
  • Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies
    Review Biomol Ther 19(4), 398-410 (2011) Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies Im-Soon Lee* Department of Biological Sciences and Center for Biotechnology Research in UBITA (CBRU), Konkuk University, Seoul 143-701, Republic of Korea Abstract Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed signifi cantly, rendering this disease of the most cur- able human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identifi cation of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specifi c therapeutic strategies for EBV- associated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases. Key Words: Classical Hodgkin lymphoma, EBV, Hodgkin and Reed-Sternberg cells INTRODUCTION and Cole, 1980), and EBV DNA/RNA can be detected in HL tissues (Brink et al., 1997), suggesting that as a primary event Lymphoma is a type of cancer involving cells of the im- in the development of this disease, EBV infection may play a mune system, and has two major categories: Hodgkin lym- very crucial role in the pathogenesis of HL.
    [Show full text]
  • Perspectiva New Perspectives on the Treatment Of
    New Perspectives on the Treatment of Differentiated Thyroid Cancer perspectiva ABSTRACT Even though differentiated thyroid carcinoma is a slow growing and usu- ally curable disease, recurrence occurs in 20–40% and cellular dedifferen- SABRINA MENDES COELHO tiation in up to 5% of cases. Conventional chemotherapy and radiotherapy DENISE PIRES DE CARVALHO have just a modest effect on advanced thyroid cancer. Therefore, dediffer- entiated thyroid cancer represents a therapeutic dilemma and a critical MÁRIO VAISMAN area of research. Targeted therapy, a new generation of anticancer treat- ment, is planned to interfere with a specific molecular target, typically a protein that is believed to have a critical role in tumor growth or progres- sion. Since many of the tumor-initiation events have already been identi- Serviço de Endocrinologia do fied in thyroid carcinogenesis, targeted therapy is a promising therapeutic Hospital Universitário Clementino tool for advanced thyroid cancer. Several new drugs are currently being Fraga Filho (SMC & MV) e Labo- tested in in vitro and in vivo studies and some of them are already being ratório de Fisiologia Endócrina used in clinical trials, like small molecule tyrosine kinase inhibitors. In this da Universidade Federal do Rio review, we discuss the bases of targeted therapies, the principal drugs de Janeiro (DPC), Rio de already tested and also options of redifferentiation therapy for thyroid car- Janeiro, RJ. cinoma. (Arq Bras Endocrinol Metab 2007;51/4:612-624) Keywords: Thyroid cancer; Redifferentiation therapy; Targeted therapy; Tyrosine kinase inhibitors RESUMO Novas Perspectivas no Tratamento do Carcinoma Diferenciado da Tireóide. Apesar de o carcinoma diferenciado da tireóide ser considerado uma doença de curso indolente e geralmente curável, recorrência tumoral ocorre em aproximadamente 20 a 40% e desdiferenciação celular, em até 5% dos casos.
    [Show full text]
  • Cancer Resistance to Treatment and Antiresistance Tools Offered By
    Casals et al. Cancer Nano (2017) 8:7 DOI 10.1186/s12645-017-0030-4 REVIEW Open Access Cancer resistance to treatment and antiresistance tools ofered by multimodal multifunctional nanoparticles Eudald Casals1†, Muriel F. Gusta1†, Macarena Cobaleda‑Siles1, Ana Garcia‑Sanz1 and Victor F. Puntes1,2,3* *Correspondence: [email protected] Abstract †Eudald Casals and Muriel F. Chemotherapeutic agents have limited efcacy and resistance to them limits today Gusta contributed equally to this work and will limit tomorrow our capabilities of cure. Resistance to treatment with antican‑ 1 Vall d’Hebron Research cer drugs results from a variety of factors including individual variations in patients and Institute (VHIR), Passeig somatic cell genetic diferences in tumours. In front of this, multimodality has appeared Vall d’Hebron 119‑129, 08035 Barcelona, Spain as a promising strategy to overcome resistance. In this context, the use of nanoparticle- Full list of author information based platforms enables many possibilities to address cancer resistance mechanisms. is available at the end of the Nanoparticles can act as carriers and substrates for diferent ligands and biologically article active molecules, antennas for imaging, thermal and radiotherapy and, at the same time, they can be efectors by themselves. This enables their use in multimodal thera‑ pies to overcome the wall of resistance where conventional medicine crash as ageing of the population advance. In this work, we review the cancer resistance mechanisms and the advantages of inorganic nanomaterials to enable multimodality against them. In addition, we comment on the need of a profound understanding of what happens to the nanoparticle-based platforms in the biological environment for those possibili‑ ties to become a reality.
    [Show full text]
  • Chemical Biology of Natural Indolocarbazole Products: 30 Years Since the Discovery of Staurosporine
    The Journal of Antibiotics (2009) 62, 17–26 & 2009 Japan Antibiotics Research Association All rights reserved 0021-8820/09 $32.00 www.nature.com/ja REVIEW ARTICLE Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine Hirofumi Nakano and Satoshi O¯ mura Staurosporine was discovered at the Kitasato Institute in 1977 while screening for microbial alkaloids using chemical detection methods. It was during the same era that protein kinase C was discovered and oncogene v-src was shown to have protein kinase activity. Staurosporine was first isolated from a culture of Actinomyces that originated in a soil sample collected in Mizusawa City, Japan. Thereafter, indolocarbazole compounds have been isolated from a variety of organisms. The biosynthesis of staurosporine and related indolocarbazoles was finally elucidated during the past decade through genetic and biochemical studies. Subsequently, several novel indolocarbazoles have been produced using combinatorial biosynthesis. In 1986, 9 years since its discovery, staurosporine and related indolocarbazoles were shown to be nanomolar inhibitors of protein kinases. They can thus be viewed as forerunners of today’s crop of novel anticancer drugs. The finding led many pharmaceutical companies to search for selective protein kinase inhibitors by screening natural products and through chemical synthesis. In the 1990s, imatinib, a Bcr-Abl tyrosine kinase inhibitor, was synthesized and, following human clinical trials for chronic myelogenous leukemia, it was approved for use in the USA in 2001. In 1992, mammalian topoisomerases were shown to be targets for indolocarbazoles. This opened up new possibilities in that indolocarbazole compounds could selectively interact with ATP- binding sites of not only protein kinases but also other proteins that had slight differences in ATP-binding sites.
    [Show full text]
  • Induction of Apoptosis by Evodiamine Involves Both Activation of Mitotic Arrest and Mitotic Slippage
    ONCOLOGY REPORTS 26: 1447-1455, 2011 Induction of apoptosis by evodiamine involves both activation of mitotic arrest and mitotic slippage LI-HONG ZHU1,3, WEI BI2, XIAO-DONG LIU3, JIE-FEN LI3, YING-YA WU3, BIAO-YAN DU3 and YU-HUI TAN3 1Department of Pathophysiology, Medical College of Jinan University, Guangzhou 510632; 2Department of Neurology, First Affiliated Hospital of Jinan University, Guangzhou 510630; 3College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510405, P.R. China Received June 2, 2011; Accepted July 7, 2011 DOI: 10.3892/or.2011.1444 Abstract. Evodiamine (Evo) is an indole quinazoline alka- Introduction loid isolated from the fruit of Evodia rutaecarpa Bentham. Previous studies have shown that Evo exhibits anti-proliferative Evodiamine (Evo) is one of the principle bioactive compounds anti-tumor activities in several cancer types, but its target(s) isolated from the dry, unripened fruit of Evodia rutaecarpa and underlying mechanism(s) of action remain unclear. In Bentham (known in Chinese as ‘wu-chu-yu’). This natural the present study, we sought to establish a cell synchroniza- compound affects many physiological processes, including tion model in order to examine the anti-proliferative and gastrointestinal tract function (1), vasorelaxation (2) and apoptotic mechanisms of Evo in the human gastric cancer cell exhibits cardiotonic effects (3) and has been used as astrin- line SGC-7901. In addition, we transfected these cells with gent, analgesic, anti-emetic and anti-inflammatory agent and full-length or non-degradable (ND) cyclinB1 to evaluate the in the treatment of hypertension (4). relationship between the induction of apoptosis and activa- Recently, Evo has been reported to possess anti-cancer tion of mitotic arrest and mitotic slippage by Evo.
    [Show full text]
  • Antikinetoplastid Activity of Indolocarbazoles from Streptomyces Sanyensis
    biomolecules Article Antikinetoplastid Activity of Indolocarbazoles from Streptomyces sanyensis 1,2, 3, 3 3 Luis Cartuche y , Ines Sifaoui y, Atteneri López-Arencibia , Carlos J. Bethencourt-Estrella , Desirée San Nicolás-Hernández 3, Jacob Lorenzo-Morales 3, José E. Piñero 3,* , Ana R. Díaz-Marrero 1,* and José J. Fernández 1,4,* 1 Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna (ULL), Avda. Astrofísico F. Sánchez 2, 38206 La Laguna, Tenerife, Spain 2 Departamento de Química y Ciencias Exactas, Sección Química Básica y Aplicada, Universidad Técnica Particular de Loja (UTPL), San Cayetano alto s/n, A.P. 1101608, Loja, Ecuador 3 Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), Departamento de Obstetricia y Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad de La Laguna, Avda. Astrofísico F. Sánchez s/n, 38206 La Laguna, Tenerife, Spain 4 Departamento de Química Orgánica, Universidad de La Laguna (ULL), Avda. Astrofísico F. Sánchez, 2, 38206 La Laguna, Tenerife, Spain * Correspondence: [email protected] (J.E.P.); [email protected] (A.R.D.-M.); [email protected] (J.J.F.) L. Cartuche and I. Sifaoui contributed equally to this work. y Received: 18 February 2020; Accepted: 17 April 2020; Published: 24 April 2020 Abstract: Chagas disease and leishmaniasis are neglected tropical diseases caused by kinetoplastid parasites of Trypanosoma and Leishmania genera that affect poor and remote populations in developing countries. These parasites share similar complex life cycles and modes of infection. It has been demonstrated that the particular group of phosphorylating enzymes, protein kinases (PKs), are essential for the infective mechanisms and for parasite survival.
    [Show full text]
  • The Synthesis of Biologically Active Indolocarbazole Natural Products Cite This: DOI: 10.1039/D0np00096e George E
    Natural Product Reports View Article Online REVIEW View Journal The synthesis of biologically active indolocarbazole natural products Cite this: DOI: 10.1039/d0np00096e George E. Chambers, a A. Emre Sayan b and Richard C. D. Brown *a Covering: up to 2020 The indolocarbazoles, in particular indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, are an important class of natural products that exhibit a wide range of biological activities. There has been a plethora of synthetic approaches to this family of natural products, leading to advances in chemical methodology, as well as affording access to molecular scaffolds central to protein kinase drug discovery programmes. In this review, we compile and summarise the synthetic approaches to the indolo[2,3-a]pyrrolo[3,4-c]carbazole Received 16th December 2020 derivatives, spanning the period from their isolation in 1980 up to 2020. The selected natural products DOI: 10.1039/d0np00096e Creative Commons Attribution-NonCommercial 3.0 Unported Licence. include indolocarbazoles not functionalised at indolic nitrogen, pyranosylated indolocarbazoles, rsc.li/npr furanosylated indolocarbazoles and disaccharideindolocarbazoles. 1 Introduction nitrogen-containing ring (Fig. 1). There are several indolocarbazole 1.1 The indolocarbazoles isomers, of which the ve most commonly isolated are the 11,12- 1.2 The indolocarbazole alkaloids and their discovery dihydroindolo[2,3-a]-carbazole (1), 5,7-dihydroindolo[2,3-b]carba- 2 Syntheses of indolocarbazoles not functionalised at zole (2), 5,8-dihydroindolo[2,3-c]carbazole (3), 5,12-dihydroindolo indolic nitrogen [3,2-a]carbazole (4) and the 5,11-dihydroindolo[3,2-b]carbazole (5). This article is licensed under a 2.1 Staurosporine aglycone (staurosporinone, 10) The indolocarbazoles have been the subject of several extensive 2.2 Arcyriaavin A (45) 2.3 Arcyriaavins B–D 3 Pyranosylated indolocarbazoles Open Access Article.
    [Show full text]
  • Targeted Inhibitors of P-Glycoprotein Increase Chemotherapeutic
    www.nature.com/scientificreports OPEN Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced Received: 15 September 2017 Accepted: 27 December 2017 mortality of multidrug resistant Published: xx xx xxxx tumor cells Amila K. Nanayakkara1,2, Courtney A. Follit1,2, Gang Chen1,2, Noelle S. Williams3, Pia D. Vogel1,2 & John G. Wise1,2 Overexpression of ATP-binding cassette (ABC) transporters is often linked to multidrug resistance (MDR) in cancer chemotherapies. P-glycoprotein (P-gp) is one of the best studied drug transporters associated with MDR. There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR by inhibiting P-glycoprotein. Using computational studies, we previously identifed several compounds that inhibit P-gp by targeting its nucleotide binding domain and avoiding its drug binding domains. Several of these compounds showed successful MDR reversal when tested on a drug resistant prostate cancer cell line. Using conventional two-dimensional cell culture of MDR ovarian and prostate cancer cells and three dimensional prostate cancer microtumor spheroids, we demonstrated here that co-administration with chemotherapeutics signifcantly decreased cell viability and survival as well as cell motility. The P-gp inhibitors were not observed to be toxic on their own. The inhibitors increased cellular retention of chemotherapeutics and reporter compounds known to be transport substrates of P-gp. We also showed that these compounds are not transport substrates of P-gp and that two of the three inhibit P-gp, but not the closely related ABC transporter, ABCG2/BCRP. The results presented suggest that these P-gp inhibitors may be promising leads for future drug development.
    [Show full text]
  • Discovery of Indolotryptoline Antiproliferative Agents by Homology-Guided Metagenomic Screening
    Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening Fang-Yuan Chang and Sean F. Brady1 Laboratory of Genetically Encoded Small Molecules, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065 Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved December 12, 2012 (received for review October 18, 2012) Natural product discovery by random screening of broth extracts family (7). Using homology-guided metagenomic library screening, derived from cultured bacteria often suffers from high rates of re- we report here the discovery, cloning, and heterologous expression dundant isolation, making it ever more challenging to identify of the indolotryptoline-based bor biosynthetic gene cluster, which novel biologically interesting natural products. Here we show that encodes for the borregomycins (Fig. 1). The borregomycins are homology-based screening of soil metagenomes can be used to generated from a branched tryptophan dimer biosynthetic pathway, 1 specifically target the discovery of new members of traditionally withonebranchleadingtoborregomycinA(), a unique indolo- tryptoline antiproliferative agent with kinase inhibitor activity, and rare, biomedically relevant natural product families. Phylogenetic – 2–4 analysis of oxy-tryptophan dimerization gene homologs found a second branch leading to borregomycins B D( ), a unique within a large soil DNA library enabled the identification and re- series of dihydroxyindolocarbazole anticancer/antibacterial agents. covery of a unique tryptophan dimerization biosynthetic gene Results and Discussion cluster, which we have termed the bor cluster. When heterolo- A single gram of soil is predicted to contain thousands of unique gously expressed in Streptomyces albus, this cluster produced an δ bacterial species, the vast majority of which remain recalcitrant to indolotryptoline antiproliferative agent with CaMKII kinase inhib- culturing in the laboratory (8).
    [Show full text]
  • The RNA Splicing Response to DNA Damage
    Biomolecules 2015, 5, 2935-2977; doi:10.3390/biom5042935 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Review The RNA Splicing Response to DNA Damage Lulzim Shkreta and Benoit Chabot * Département de Microbiologie et d’Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-819-821-8000 (ext. 75321); Fax: +1-819-820-6831. Academic Editors: Wolf-Dietrich Heyer, Thomas Helleday and Fumio Hanaoka Received: 12 August 2015 / Accepted: 16 October 2015 / Published: 29 October 2015 Abstract: The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging.
    [Show full text]
  • Poisoning of Topoisomerase I by an Antitumor Indolocarbazole Drug
    [CANCER RESEARCH 59, 52–55, January 1, 1999] Advances in Brief Poisoning of Topoisomerase I by an Antitumor Indolocarbazole Drug: Stabilization of Topoisomerase I-DNA Covalent Complexes and Specific Inhibition of the Protein Kinase Activity1 Emmanuel Labourier, Jean-Franc¸ois Riou,2 Michelle Prudhomme, Carolina Carrasco, Christian Bailly, and Jamal Tazi Institut de Ge´ne´tique Mole´culaire, Universite´ de Montpellier II, 34293 Montpellier cedex [E. L., J. T.]; Rhoˆne-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 94403 Vitry sur Seine [J-F. R.]; Synthe`se Electrosynthe`se et Etude de Syste`mes a` Inte`neˆt Biologique, Universite´ Blaise Pascal, 63177 Aubie`re cedex [M. P.]; and Laboratoire de Pharmacologie Mole´culaire Antitumorale du Centre Oscar Lambret et U-124 INSERM, 59045 Lille cedex [C. C., C. B.], France Abstract we have investigated the effect of the compound on wild type topoi- somerase I that acts essentially as a DNA relaxing enzyme and the We have investigated the mechanism of topoisomerase I inhibition by mutant enzyme Y723F that acts selectively as a phosphotransferase. an indolocarbazole derivative, R-3. The compound is cytotoxic to P388 In the present study, we show that the antitumor indolocarbazole leukemia cells, but not to P388CPT5 camptothecin-resistant cells having a compound R-3 inhibits both the DNA cleavage/ligation and kinase deficient topoisomerase I. R-3 can behave both as a specific topoisomerase I inhibitor trapping the cleavable complexes and as a nonspecific inhibitor activities of topoisomerase I. This is the first ligand known thus far of a DNA-processing enzyme acting via DNA binding.
    [Show full text]
  • Killing Cells by Targeting Mitosis
    Cell Death and Differentiation (2012) 19, 369–377 & 2012 Macmillan Publishers Limited All rights reserved 1350-9047/12 www.nature.com/cdd Review Killing cells by targeting mitosis E Manchado1, M Guillamot1 and M Malumbres*,1 Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell–cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic. Cell Death and Differentiation (2012) 19, 369–377; doi:10.1038/cdd.2011.197; published online 6 January 2012 Facts We need to identify and characterize specific biomarkers for a better definition of patients that may benefit from Extensive understanding of cell cycle regulation has led to therapeutic strategies targeting mitosis.
    [Show full text]