DOCSLIB.ORG

Wo 2008/039482 A2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Wo 2008/039482 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 3 April 2008 (03.04.2008) PCT WO 2008/039482 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/57 (2006.01) kind of national protection available): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (21) International Application Number: CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, PCT/US2007/020753 ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (22) International Filing Date: IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 26 September 2007 (26.09.2007) LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (25) Filing Language: English PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, (26) Publication Language: English TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (30) Priority Data: 60/847,173 26 September 2006 (26.09.2006) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): THE kind of regional protection available): ARIPO (BW, GH, REGENTS OF THE UNIVERSITY OF CALIFORNIA GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, [US/US]; 1111 Franklin Street, Fifth Floor, Oakland, CA ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 94607-5200 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (72) Inventor; and PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (75) Inventor/Applicant (for US only): LEE, Eva, Y-H P. GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). [US/US]; 128 Sprague Hall, Irvine, CA 92697 (US). (74) Agents: DE BERG, Lisa, G. et al; Casimir Jones, S.C., Published: 101 Howard Street, Suite 350, San Francisco, CA 94105 — without international search report and to be republished (US). upon receipt of that report (54) Title: METHODS AND COMPOSITIONS FOR CANCER PREVENTION AND TREATMENT (57) Abstract: The present invention relates to methods and compositions for cancer prevention and treatment. In particular, the present invention provides methods and compositions for modulating, studying, preventing and treating progesterone receptor related carcinogenesis with anti-progesterones and anti-estrogens. METHODS AND COMPOSITIONS FOR CANCER PREVENTION AND TREATMENT This application claims priority to United States Provisional Application 60/847,173, filed on September 26, 2006. This application was made with government support under grant number CA049649 awarded by NCI and grant number DAMD 17-02-1 - 0694 awarded by the DOD. The government has certain rights in the invention. FIELD OF THE INVENTION The present invention relates to methods and compositions for cancer prevention and treatment hi particular, the present invention provides methods and compositions for modulating, studying, preventing and treating progesterone receptor related carcinogenesis with anti-progesterones and anti-estrogens. BACKGROUND OF THE INVENTION Breast cancer incidence in women has increased from one in 20 in 1960 to one in seven today. Every two minutes a woman in the United States is diagnosed with breast cancer. In 2005, it was estimated that about 212,000 new cases of invasive breast cancer would be diagnosed, along with 58,000 new cases of non-invasive breast cancer, and 40,000 women were expected to die from this disease. The exact cause of breast cancer is not known, however changes in certain genes make women more susceptible to breast cancer. Individuals with mutations in the breast cancer gene 1 (BRCAl) and gene 2 (BRCA2), for example, are predisposed to breast and ovarian cancers and run a high risk of having the disease. BRCAl participates in several cellular processes, but its function in suppressing carcinogenesis of ovarian hormone-sensitive tissues remains unclear. Historically, estrogen and the estrogen receptor and their function in breast cancer have attracted considerable attention. However, the underlying mechanisms of cancer are not fully understood. The current therapies for breast cancer include chemotherapy, radiation therapy, surgery to remove a woman's ovaries to decrease production of the hormones estrogen and progesterone, surgery to remove the tumors, and combinations thereof. What is needed are novel ways of studying, understanding, treating, and above all, preventing breast and other cancers. SUMMARY OF THE INVENTION The present invention relates to methods and compositions for cancer prevention and treatment. In particular, the present invention provides methods and compositions for modulating, studying, preventing and treating progesterone receptor related carcinogenesis with anti-progesterones and anti-estrogens. Mutations in BRCAl are associated with an increase in breast and ovarian cancer risks (Miki et al., 1994, Science 266:66). Reduced BRCAl expression due to promoter methylation is also found in sporadic breast and ovarian cancers (Thompson et al., 1995, Nat. Genet. 9:444). BRCAl maintains genome stability by participating in DNA damage repair, cell cycle checkpoint control and transcriptional regulation (Ting et al., 2004, DNA Repair 3:935; Turner et al., 2004, Nat. Rev. Cancer 4:814). The specific suppression of breast and ovarian carcinogenesis by the pleiotropic BRCAl tumor suppressor may be due to its regulatory roles over estrogen receptor α (ERa) and the progesterone receptor (PR) (Fan et al., 1999, Science 284:1354; Zheng et al., 2001, Proc. Natl. Acad. Sci. 98:9587; Razandi et al., 2004, MoI. Cell. Biol. 24:5900; Ma et al., 2006, MoI. Endocrinol. 20:14). ERa and PR play important roles in breast development (Henninghausen et al., 2005, Nat. Rev. MoI. Cell.Biol. 6:715; Li et al., 2004, Mech. Ageing Dev. 125:669). In ERa knockout mice, ductal elongation and pregnancy-induced proliferation of mammary gland are severely affected (Mallepell et al., 2006, Proc. Natl. Acad. Sci. 103:2196). In mice lacking PR-B, the long form of PR, ductal elongation is normal but pregnancy-induced ductal branching, and alveolar proliferation and differentiation are defective (Mulac- Jericevic et al., 2003, Proc. Natl. Acad. Sci. 100:9744). BRCAl modulates the activities of these nuclear hormone receptors through three distinct mechanisms: ligand-dependent, and - independent transcription activities of ERa and PR, as well as non-genomic function of ERa (Fan et al., 1999, Science 284:1354; Zheng et al., 2001, Proc. Natl. Acad. Sci. 98:9587; Razandi et al., 2004, MoI. Cell. Biol. 24:5900; Ma et al., 2006, MoI. Endocrinol. 20:14). The contribution of ER and PR in BRCAl -mediated carcinogenesis remains unclear, however. Progesterone and estrogen hormone replacement therapy in postmenopausal women is associated with higher proliferation index and significantly greater breast cancer risk (Million Women Study, 2003, Lancet 362:419; Rossouw et al., 2002, JAMA 288:321; Lee et al., 2006, Int. J. Cancer 118:1285). The two PR isoforms, PR-A and PR-B are generated through alternative promoter usage of a single gene (Li et al., 2004, Mech. Ageing Dev. 125:669). Introduction of extra PR-A transgene, the short form of PR in mice, leads to abnormal mammary development and ductal hyperplasia (Shyamala et al., 1998, Proc. Natl. Acad. Sci. 95:696). Immunostaining shows increased PR expression in normal mammary epithelial cells (MECs) of breast cancer patients carrying a germ line mutation of BRCAl (King et al., 2004, Cancer Res. 64:505 1). Normally, PR stability is regulated by proteosome; a progesterone receptor becomes polyubiquinated upon exposure to a ligand and is subsequently targeted for degradation by proteosome (Lange et al., 2000, Proc. Natl. Acad. Sci. 97:1032). The present invention demonstrates that progesterone receptor stability is related to breast cancer, and preventing and/or treating progesterone related breast cancer with anti- progesterones provides a molecular framework for the study and prevention of cancer in BRCAl carriers by using anti-progesterones as a chemopreventive strategy for PR related cancers. Anti-progesterones, such as pure progesterone receptor antagonists (PAs, typically associated with compounds that exhibit no agonistic effect on PR) or selective progesterone receptor modulators (SPRMs, typically associated with compounds that exhibit both antagonistic and agonist effects of PR) (hereinafter, PA and SPRM compounds will be referred to under the general acronym of "SPRM") are those compounds, drugs, or agents that modulate the activity of the progesterone receptor (Chabbert-buffet et al., 2005, Hum. Repro. Update 11:293-307, incorporated herein in its entirety). Although the SPRMs have no immediate structural relationship with progesterone, they are stereochemical^ similar to this hormone and interact with its receptors. The study of BRCAl mutations in vitro and in an in vivo mouse model described herein demonstrates the efficacy of using SPRMs to modulate tumorigenesis. Using mice models, it is shown that BRCAl/p53 defective mammary glands of nulliparous mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype only seen during pregnancy in normal mice. The majority of BRCAl mediated tumors in humans harbor p53 mutations as well (Ting et al., 2004, DNA Repair 3:935; Turner et al., 2004, Nat. Rev. Cancer 4:814). Progesterone receptors, but not estrogen receptors, are over-expressed in MECs of conditional BRCAl/p53, but not p53 knockout mice; therefore, progesterone is a potent mitogen for BRCAl/p53 defective MECs specifically. Ligand-induced polyubiquitination and proteosome-mediated degradation of PRs are aberrant in breast epithelial cells with BRCAl knockdown, leading to stabilization and accumulation of PR. Treatment with the SPRM mifepristone prevents tumorigenesis in mice carrying mutated BRCAl/p53 alleles, thereby showing a critical role of PR in BRCAl mediated tumorigenesis.
Load more

Recommended publications
  • Current Strategies of Cancer Chemoprevention: 13Th Sapporo Cancer Seminar
    ICANCER RESEARCH54, 3315—3318,June15, 19941 Meeting Report Current Strategies of Cancer Chemoprevention: 13th Sapporo Cancer Seminar The broad concept of chemoprevention applies to the prevention of either antimutagenic or antimitogenic. Antioxidants, because of their clinical cancer by the administration of pharmaceuticals or dietary similar mechanism of action, have been grouped separately as a third constituents. In recent years there has been a rapid expansion of basic class. Antioxidants are both antimutagenic and antimitogenic. research on mechanisms of chemoprevention, and more and more candidate compounds are entering clinical trials. It is therefore timely Clinical Trials of Chemopreventive Agents that the subject of the 13th Sapporo Cancer Seminar held on July 6—9, 1993, was “CurrentStrategies of Cancer Chemoprevention.― The Head and Neck. Dr. W-K. Hong (University of Texas M. D. Seminar was organized by Drs. H. Fujiki, H. Kobayashi, L. W. Anderson Cancer Center, Houston, TX) reviewed the successful use Wattenberg, C. W. Boone, and 0. J. Kelloff. of 13-cRA against the development of upper aerodigestive tract neo plasia. In trials in human oral premalignancy, or leukoplakia, 13-cPA Chemoprevention by Minor Nonnutrient Constituents achieved a significant objective response rate of 67% (3). In an of the Diet adjuvant trial to prevent second primary tumors in patients initially “cured―ofhead and neck squamous cell carcinoma, 13-cPA signifi Dr. L. Wattenberg (University of Minnesota, Minneapolis, MN) cantly reduced the high incidence of these usually fatal second ma described the growing awareness in recent years that dietary nonnu lignancies (4). Moderate to severe side effects of 13-cPA include: skin trient compounds can have extremely important effects on the conse dryness (63% versus 8% placebo); cheilitis (24% versus 2% placebo); quences of exposure to carcinogens, drugs, and an assortment of other and conjunctivitis (18% versus 8% placebo).
    [Show full text]
  • New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Acute Effect
    J Pharmacol Sci 109, 334 – 340 (2009)3 Journal of Pharmacological Sciences ©2009 The Japanese Pharmacological Society Forum Minireview New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Acute Effects of Female Hormones on Cardiac Ion Channels and Cardiac Repolarization Junko Kurokawa1,*, Takeshi Suzuki2, and Tetsushi Furukawa1 1Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan 2Faculty of Pharmacy, Division of Basic Biological Sciences, Keio University, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512, Japan Received October 16, 2008; Accepted December 6, 2008 Abstract. Regulation of cardiac ion channels by sex hormones accounts for gender differences in susceptibility to arrhythmias associated with QT prolongation (TdP). Women are more prone to develop TdP than men with either congenital or acquired long-QT syndrome. The risk of drug- induced TdP varies during the menstrual cycle, suggesting that dynamic changes in levels of ovarian steroids, estradiol and progesterone, have cyclical effects on cardiac repolarization. Although increasing evidence suggests that the mechanism of this involves effects of female hormones on cardiac repolarization, it has not been completely clarified. In addition to well- characterized transcriptional regulation of cardiac ion channels and their modifiers through nuclear hormone receptors, we recently reported that physiological levels of female hormones modify functions of cardiac ion channels in mammalian hearts. In this review, we introduce our recent findings showing that physiological levels of the two ovarian steroids have opposite effects on cardiac repolarization. These findings may explain the dynamic changes in risk of arrhythmia in women during the menstrual cycle and around delivery, and they provide clues to avoiding potentially lethal arrhythmias associated with QT prolongation.
    [Show full text]
  • Phytochem Referenzsubstanzen
    High pure reference substances Phytochem Hochreine Standardsubstanzen for research and quality für Forschung und management Referenzsubstanzen Qualitätssicherung Nummer Name Synonym CAS FW Formel Literatur 01.286. ABIETIC ACID Sylvic acid [514-10-3] 302.46 C20H30O2 01.030. L-ABRINE N-a-Methyl-L-tryptophan [526-31-8] 218.26 C12H14N2O2 Merck Index 11,5 01.031. (+)-ABSCISIC ACID [21293-29-8] 264.33 C15H20O4 Merck Index 11,6 01.032. (+/-)-ABSCISIC ACID ABA; Dormin [14375-45-2] 264.33 C15H20O4 Merck Index 11,6 01.002. ABSINTHIN Absinthiin, Absynthin [1362-42-1] 496,64 C30H40O6 Merck Index 12,8 01.033. ACACETIN 5,7-Dihydroxy-4'-methoxyflavone; Linarigenin [480-44-4] 284.28 C16H12O5 Merck Index 11,9 01.287. ACACETIN Apigenin-4´methylester [480-44-4] 284.28 C16H12O5 01.034. ACACETIN-7-NEOHESPERIDOSIDE Fortunellin [20633-93-6] 610.60 C28H32O14 01.035. ACACETIN-7-RUTINOSIDE Linarin [480-36-4] 592.57 C28H32O14 Merck Index 11,5376 01.036. 2-ACETAMIDO-2-DEOXY-1,3,4,6-TETRA-O- a-D-Glucosamine pentaacetate 389.37 C16H23NO10 ACETYL-a-D-GLUCOPYRANOSE 01.037. 2-ACETAMIDO-2-DEOXY-1,3,4,6-TETRA-O- b-D-Glucosamine pentaacetate [7772-79-4] 389.37 C16H23NO10 ACETYL-b-D-GLUCOPYRANOSE> 01.038. 2-ACETAMIDO-2-DEOXY-3,4,6-TRI-O-ACETYL- Acetochloro-a-D-glucosamine [3068-34-6] 365.77 C14H20ClNO8 a-D-GLUCOPYRANOSYLCHLORIDE - 1 - High pure reference substances Phytochem Hochreine Standardsubstanzen for research and quality für Forschung und management Referenzsubstanzen Qualitätssicherung Nummer Name Synonym CAS FW Formel Literatur 01.039.
    [Show full text]
  • Posttranslational Modifications of the Mineralocorticoid Receptor And
    REVIEW published: 28 May 2021 doi: 10.3389/fmolb.2021.667990 Posttranslational Modifications of the Mineralocorticoid Receptor and Cardiovascular Aging Yekatarina Gadasheva, Alexander Nolze and Claudia Grossmann* Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin- angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during Edited by: aging and cardiovascular diseases without correlating changes of its ligand Thorsten Pfirrmann, Health and Medical University aldosterone. There is growing evidence that the MR can be enzymatically and non- Potsdam, Germany enzymatically modified and that these modifications contribute to ligand-independent Reviewed by: modulation of MR activity. Modifications reported so far include phosphorylation, Ritu Chakravarti, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and University of Toledo, United States Frederic Jaisser, oxidative stress. This review focuses on the different posttranslational modifications Institut National De La Santé Et De La of the MR, their impact on MR function and degradation and the possible implications Recherche Médicale (INSERM), France for cardiovascular aging and diseases.
    [Show full text]
  • NIH Public Access Author Manuscript Drug Metab Rev
    NIH Public Access Author Manuscript Drug Metab Rev. Author manuscript; available in PMC 2008 June 10. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Drug Metab Rev. 2006 ; 38(1-2): 89±116. THE BIOLOGICAL ACTIONS OF DEHYDROEPIANDROSTERONE INVOLVES MULTIPLE RECEPTORS Stephanie J. Webb, Thomas E. Geoghegan, and Russell A. Prough Department of Biochemistry & Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA Kristy K. Michael Miller Department of Chemistry, University of Evansville, Evansville, Indiana, USA Abstract Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the peroxisome proliferators activated receptor alpha, pregnane X receptor, and estrogen receptor by DHEA and its metabolites have been demonstrated. Several membrane- associated receptors have also been elucidated leading to additional mechanisms by which DHEA may exert its biological effects. This review will provide an overview of the receptor multiplicity involved in the biological activity of this sterol. Keywords Dehydroepiandrosterone; DHEA; Hormone receptors; 11β-hydroxysteroid dehydrogenases; Cytochrome P450; Peroxisome proliveration; PPARα; PXR; Estrogen receptor; Insulin growth factor binding protein 1 INTRODUCTION The metabolism of sterols by cytochromes P450 and the mechanisms of hydroxylation of sterols were among the research topics of great interest to Dr. David Kupfer. On many occasions, I contacted David for his opinion about experiments I was pursuing and the discussions always led to his informing me of the current work in his laboratory.
    [Show full text]
  • Cannabinoid Type 2 Receptor Agonist JWH-133, Attenuates Okadaic Acid
    Life Sciences 217 (2019) 25–33 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Cannabinoid type 2 receptor agonist JWH-133, attenuates Okadaic acid induced spatial memory impairment and neurodegeneration in rats T ⁎ Murat Çakıra, , Suat Tekinb, Züleyha Doğanyiğitc, Yavuz Erdend, Merve Soytürkb, Yılmaz Çiğremişe, Süleyman Sandalb a Faculty of Medicine, Department of Physiology, University of Bozok, Yozgat 66200, Turkey b Faculty of Medicine, Department of Physiology, University of Inonu, Malatya 44280, Turkey c Faculty of Medicine, Department of Histology and Embryology, University of Bozok, Yozgat 66200, Turkey d Department of Molecular Biology and Genetics, Faculty of Science, Bartın University, Bartın 74100, Turkey e Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, Malatya 44280, Turkey ARTICLE INFO ABSTRACT Keywords: Aim: Cannabinoid system has various physiological roles such as neurogenesis, synaptic plasticity and emotional Alzheimer's disease state regulation in the body. The presence of cannabinoid type 2 receptor (CB2), a member of the cannabinoid Okadaic acid system, was detected in different regions of the brain. CB2 receptor plays a role in neuroinflammatory and Cannabinoid type 2 receptor neurodegenerative processes. We aimed to determine the possible effect of CB2 agonist JWH-133 in Okadaic acid JWH-133 (OKA)-induced neurodegeneration model mimicking Alzheimer's Disease (AD) through tau pathology. Materials and methods: In this study, 40 Sprague Dawley male rats were divided into 4 groups (Control, Sham, OKA, OKA + JWH-133). Bilateral intracerebroventricular (icv) injection of 200 ng OKA was performed in the OKA group. In the OKA + JWH-133 group, injection of JWH-133 (0.2 mg/kg) was performed intraperitoneally for 13 days different from the group of OKA.
    [Show full text]
  • ENGAGEMENT of the INSULIN-SENSITIVE PATHWAY in the STIMULATION of GLUCOSE TRANSPORT by A-LIPOIC ACID
    ENGAGEMENT OF THE INSULIN-SENSITIVE PATHWAY IN THE STIMULATION OF GLUCOSE TRANSPORT BY a-LIPOIC ACID. Karen Lynne Yaworsky A M. Sc. thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Biochemistry University of Toronto O Copyright by Karen Yaworsky 1999 National Library Bibliothèque nationale of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services senrices bibliographiques 395 Wellington Street 395, rue Wellington Ottawa ON KIA ON4 OtiawaON K1AON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distibute or sel1 reproduire, prêter, distribuer ou copies of ths thesis in microfonn, vendre des copies de cette thèse sous paper or electronic fomats. la fome de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur consenre la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels may be prhted or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. ENGAGEMENT OF THE INSULIN-SENSITIVE PATHWAY IN THE STIMULATION OF GLUCOSE TRANSPORT BY a-LIPOIC ACID. A MeSc. thesis by Karen Lynne Yaworsky submitted in conformity with the requirements for the degree of Master of Science, Graduate Department of Biochemistry, University of Toronto, 1999. ABSTRACT A pnmary metabolic response to insulin is the acute stimulation of glucose transport in muscle and adipose tissue.
    [Show full text]
  • Molecular Mechanisms and Regulation of Cold Sensing
    Molecular mechanisms and regulation of cold sensing A dissertation submitted to the Division of Research and Advanced Studies Of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) in the Neuroscience Graduate Program in the College of Medicine By Ignacio Sarria B.A. St. Thomas University, Miami, Florida 2006 October 2011 Dissertation Committee: Jianguo Gu, Ph.D., Advisor Steve Kleene, Ph.D., Committee Chair: Mark Baccei, Ph.D. Jun-Ming Zhang, M.D, Ph.D. David Richards, Ph.D. Sarria, I General Abstract TRPM8 is the principal sensor of cold temperatures in mammalian primary sensory neurons. Cold temperatures 28~8°C and the cooling compound menthol activate TRPM8. TRPM8 is expressed on nociceptive and non-nociceptive primary sensory neurons and mediates innocuous and painful cold sensations. Using calcium imaging, I examined menthol responses and role of protein kinases in two functionally distinct populations of cold-sensing DRGs that use TRPM8 receptors to convey innocuous (menthol-sensitive/capsaicin-insensitive, MS/CI) and noxious (menthol-sensitive/capsaicin-sensitive, MS/CS) cold sensation. PKC activation decreased menthol response in all neurons. MS/CI neurons had larger menthol responses with greater adaptation and adaptation was attenuated by blocking PKC and CaMKII. In contrast MS/CS neurons had smaller menthol responses with less adaptation that was not affected by blocking PKC or CaMKII. In both MS/CI and MS/CS neurons, menthol responses were not affected by PKA activation or inhibition. Taken together, these results suggest that TRPM8- mediated responses are different between non-nociceptive-like and nociceptive-like neurons (Chapter II).
    [Show full text]
  • NORTHWESTERN UNIVERSITY Luteinizing Hormone Receptor Signaling Regulates MAP2D Phosphorylation in Preovulatory Granulosa Cells A
    NORTHWESTERN UNIVERSITY Luteinizing Hormone Receptor Signaling Regulates MAP2D Phosphorylation in Preovulatory Granulosa Cells A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS for the degree DOCTOR OF PHILOSOPHY Field of Cell and Molecular Biology Integrated Graduate Program in Life Sciences By Maxfield Patrick Flynn CHICAGO, ILLINOIS December 2008 2 © Copyright by Maxfield P. Flynn 2007 All Rights Reserved 3 ABSTRACT Luteinizing Hormone Receptor Signaling Regulates MAP2D Phosphorylation in Preovulatory Granulosa Cells Maxfield P. Flynn The actions of luteinizing hormone (LH) to induce ovulation and luteinization of preovulatory follicles are mediated principally by activation of cAMP-dependent protein kinase (PKA) in granulosa cells. PKA activity is targeted to specific cellular locations by A-kinase anchoring proteins (AKAPs). I previously showed that follicle-stimulating hormone (FSH) induces expression of the AKAP microtubule-associated protein (MAP) 2D and that MAP2D co- immunoprecipitates with PKA regulatory subunits in rat granulosa cells. Here I describe a rapid and targeted dephosphorylation of MAP2D at Thr256/Thr259 after treatment with LH receptor agonist hCG. This event is mimicked by treatment with forskolin or a cAMP analog and blocked by the PKA inhibitor myristoylated-PKI, indicating a role for PKA signaling in phospho- regulation of granulosa cell MAP2D. I show that Thr256/Thr259 dephosphorylation is blocked by the protein phosphatase (PP) 2A inhibitor okadaic acid and demonstrate interactions between MAP2D and PP2A by co-immunoprecipitation and microcystin-agarose pulldown. I also show that MAP2D interacts with glycogen synthase kinase (GSK) 3β and is phosphorylated at Thr256/Thr259 by this kinase in the basal state.
    [Show full text]
  • The Wonderful Activities of the Genus Mentha: Not Only Antioxidant Properties
    molecules Review The Wonderful Activities of the Genus Mentha: Not Only Antioxidant Properties Majid Tafrihi 1, Muhammad Imran 2, Tabussam Tufail 2, Tanweer Aslam Gondal 3, Gianluca Caruso 4,*, Somesh Sharma 5, Ruchi Sharma 5 , Maria Atanassova 6,*, Lyubomir Atanassov 7, Patrick Valere Tsouh Fokou 8,9,* and Raffaele Pezzani 10,11,* 1 Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar 4741695447, Iran; [email protected] 2 University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore 54600, Pakistan; [email protected] (M.I.); [email protected] (T.T.) 3 School of Exercise and Nutrition, Deakin University, Victoria 3125, Australia; [email protected] 4 Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici (Naples), Italy 5 School of Bioengineering & Food Technology, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India; [email protected] (S.S.); [email protected] (R.S.) 6 Scientific Consulting, Chemical Engineering, University of Chemical Technology and Metallurgy, 1734 Sofia, Bulgaria 7 Saint Petersburg University, 7/9 Universitetskaya Emb., 199034 St. Petersburg, Russia; [email protected] 8 Department of Biochemistry, Faculty of Science, University of Bamenda, Bamenda BP 39, Cameroon 9 Department of Biochemistry, Faculty of Science, University of Yaoundé, NgoaEkelle, Annex Fac. Sci., Citation: Tafrihi, M.; Imran, M.; Yaounde 812, Cameroon 10 Phytotherapy LAB (PhT-LAB), Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Tufail, T.; Gondal, T.A.; Caruso, G.; Via Ospedale 105, 35128 Padova, Italy Sharma, S.; Sharma, R.; Atanassova, 11 AIROB, Associazione Italiana per la Ricerca Oncologica di Base, 35128 Padova, Italy M.; Atanassov, L.; Valere Tsouh * Correspondence: [email protected] (G.C.); [email protected] (M.A.); [email protected] (P.V.T.F.); Fokou, P.; et al.
    [Show full text]
  • Regulation of Cytochrome P450 (CYP) Genes by Nuclear Receptors Paavo HONKAKOSKI*1 and Masahiko NEGISHI† *Department of Pharmaceutics, University of Kuopio, P
    Biochem. J. (2000) 347, 321–337 (Printed in Great Britain) 321 REVIEW ARTICLE Regulation of cytochrome P450 (CYP) genes by nuclear receptors Paavo HONKAKOSKI*1 and Masahiko NEGISHI† *Department of Pharmaceutics, University of Kuopio, P. O. Box 1627, FIN-70211 Kuopio, Finland, and †Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, U.S.A. Members of the nuclear-receptor superfamily mediate crucial homoeostasis. This review summarizes recent findings that in- physiological functions by regulating the synthesis of their target dicate that major classes of CYP genes are selectively regulated genes. Nuclear receptors are usually activated by ligand binding. by certain ligand-activated nuclear receptors, thus creating tightly Cytochrome P450 (CYP) isoforms often catalyse both formation controlled networks. and degradation of these ligands. CYPs also metabolize many exogenous compounds, some of which may act as activators of Key words: endobiotic metabolism, gene expression, gene tran- nuclear receptors and disruptors of endocrine and cellular scription, ligand-activated, xenobiotic metabolism. INTRODUCTION sex-, tissue- and development-specific expression patterns which are controlled by hormones or growth factors [16], suggesting Overview of the cytochrome P450 (CYP) superfamily that these CYPs may have critical roles, not only in elimination CYPs constitute a superfamily of haem-thiolate proteins present of endobiotic signalling molecules, but also in their production in prokaryotes and throughout the eukaryotes. CYPs act as [17]. Data from CYP gene disruptions and natural mutations mono-oxygenases, with functions ranging from the synthesis and support this view (see e.g. [18,19]). degradation of endogenous steroid hormones, vitamins and fatty Other mammalian CYPs have a prominent role in biosynthetic acid derivatives (‘endobiotics’) to the metabolism of foreign pathways.
    [Show full text]
  • Effects of the Marine Biotoxins Okadaic Acid and Dinophysistoxins on Fish
    Journal of Marine Science and Engineering Review Effects of the Marine Biotoxins Okadaic Acid and Dinophysistoxins on Fish Mauro Corriere 1,2 , Lucía Soliño 1,3 and Pedro Reis Costa 1,3,* 1 IPMA—Portuguese Institute for the Sea and Atmosphere, Av. Brasília, 1449-006 Lisbon, Portugal; [email protected] (M.C.); [email protected] (L.S.) 2 CIRSA—Centro Interdipartimentale di Ricerca per le Scienze Ambientali, Università di Bologna, Via Sant’Alberto, 163-48100 Ravenna, Italy 3 CCMAR—Centre of Marine Sciences, University of Algarve, Campus of Gambelas, 8005-139 Faro, Portugal * Correspondence: [email protected] Abstract: Natural high proliferations of toxin-producing microorganisms in marine and freshwater environments result in dreadful consequences at the socioeconomically and environmental level due to water and seafood contamination. Monitoring programs and scientific evidence point to harmful algal blooms (HABs) increasing in frequency and intensity as a result of global climate alterations. Among marine toxins, the okadaic acid (OA) and the related dinophysistoxins (DTX) are the most frequently reported in EU waters, mainly in shellfish species. These toxins are responsible for human syndrome diarrhetic shellfish poisoning (DSP). Fish, like other marine species, are also exposed to HABs and their toxins. However, reduced attention has been given to exposure, accumulation, and effects on fish of DSP toxins, such as OA. The present review intends to summarize the current knowledge of the impact of DSP toxins and to identify the main issues needing further research. From data reviewed in this work, it is clear that exposure of fish to DSP toxins causes a range of negative effects, from behavioral and morphological alterations to death.
    [Show full text]