Vitamin D and Estrogen Action in Bone: Concerted Role for hnRNPs in the C Family

Summary

Principal Investigator: John S Adams
Abstract: DESCRIPTION (provided by applicant): Twenty-five years ago we began to investigate an outbreak of rachitic bone disease in adolescent, female New World primates residing at the Los Angles Zoo. Our investigation of this "experiment of nature" and that of an adolescent human female with a similar phenotype led us to the discovery of a novel means for vitamin D and estrogen resistance in primates, including man. We coined these resistance-causing proteins the vitamin D response element binding protein (VDRE-BP) and estrogen response element binding (ERE-BP) for their ability to compete in trans with the liganded vitamin D receptor (VDR) and estrogen receptor 1 (ER1) for their cognate response elements, identifying them as nucleic acid binding proteins in the heterogeneous nuclear ribonucleoprotein C (hnRNPC) family. Recent work has led us to realize that the ability of these hnRNPs to alter steroid hormone-directed gene expression is not limited to their dominant-negative actions at the level of transcription. By virtue of their capacity to interact with single-strand DNA (ssDNA), ssRNA as well as double- strand DNA (dsDNA), these hnRNPs have the potential to exert control over gene expression at multiple sites in the cell. Here we theorize that a specific hnRNP can act as a multi-site participant in the synchronized expression of a single gene product by way of regulating, in succession, chromatin remodeling (ssDNA binding), transcription (dsDNA binding), splicing (ssDNA and ssRNA binding) and microRNA (miRNA;ssRNA binding). Because both the human and subhuman primate experiments of nature in hnRNP overexpression we have studied resulted in coincident vitamin D- and estrogen-antagonism on the growing skeleton of adolescent females, here we will concentrate on growing bone and the osteoblast as natural targets for these hnRNPs. Three specific aims are proposed: 1) using chromatin modification/precipitation, over/under expression and novel cell free translation technologies, explore the impact of hnRNPs on the cells responsible for 1,25- dihydroxyvitamin D and estradiol-driven bone growth;2) employ new RNA immunoprecipitation and micro- RNA methodology to study the versatility of these hnRNPS to control transcript splicing and handling by directed binding to RNA products of the same gene whose expression is simultaneously regulated at the level of chromatin remodeling and transcription;and 3) ascertain the composite effect of these hnRNPs on the growing, adolescent skeleton by targeted transgenic overexpression of the VDRE-BP and ERE-BP hnRNPs in mouse bone. It is our expectation that the proposed research will pave the way to a mechanistic understanding of how these multi-functional hnRNPs control the process of sterol/steroid hormone-regulated gene expression in growing bone and delineate novel points of potential therapeutic intervention in that process. PUBLIC HEALTH RELEVANCE: Vitamin D and estrogen are two steroid hormones long recognized for their ability to influence the growing skeleton. Twenty five years ago we began to investigate an outbreak of rickets in adolescent, female New World primates residing at the Los Angeles Zoo, identifying proteins in the heterogeneous nuclear ribonucleoprotein C (hnRNPC) family, the vitamin D response element binding protein (VDRE-BP) and estrogen response element binding (ERE-BP) which caused resistance to the actions vitamin D and estrogen hormones on the skeleton. By virtue of their capacity to interact with single-strand DNA (ssDNA), ssRNA as well as double- strand DNA (dsDNA), we have planned experiments to test our theory that the VDRE-BP and ERE-BP can act in bone as a multi-site participant in the synchronized expression of a single gene product by way of regulating, in succession, i) chromatin remodeling, ii) transcription, iii) transcript splicing and iv) transcript handling.
Funding Period: 1990-01-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein
    Hong Chen
    Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute, Cedars Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA
    J Biol Chem 281:39114-20. 2006
  2. pmc Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts
    Thomas S Lisse
    Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, CA, USA
    J Bone Miner Res 28:1478-88. 2013
  3. pmc A new regulator of osteoclastogenesis: estrogen response element-binding protein in bone
    Hong Chen
    Veterans Administration Medical Center and Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
    J Bone Miner Res 26:2537-47. 2011
  4. pmc Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling
    Thomas S Lisse
    Department of Orthopaedic Surgery and Molecular Biology Institute, David Geffen School of Medicine at UCLA, 615 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Steroids 76:331-9. 2011
  5. pmc Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling
    Thomas S Lisse
    Orthopaedic Hospital Research Center, University of California Los Angeles, 615 Charles E Young Dr, South Los Angeles, CA 90095, USA
    FASEB J 25:937-47. 2011
  6. pmc Update in vitamin D
    John S Adams
    UCLA Orthopaedic Hospital Research Center, 615 Charles Young Drive South, Room 410E, Los Angeles, California 90095 7358, USA
    J Clin Endocrinol Metab 95:471-8. 2010
  7. pmc Vitamin d-directed rheostatic regulation of monocyte antibacterial responses
    John S Adams
    Orthopaedic Hospital Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, 90095, USA
    J Immunol 182:4289-95. 2009
  8. pmc Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro
    Hong Chen
    Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Endocrinology 150:2429-35. 2009
  9. pmc Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation
    Nancy Liu
    Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, 615 Charles E Young Drive South, Los Angeles, California 90095, USA
    Endocrinology 149:4799-808. 2008
  10. pmc Back to the future: a new look at 'old' vitamin D
    Rene F Chun
    Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, 615 Charles E Young Drive South, Los Angeles, California 90095, USA
    J Endocrinol 198:261-9. 2008

Research Grants

  1. Sex Steroids and Runx Signaling in Bone
    Baruch Frenkel; Fiscal Year: 2013
  2. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
  3. Serotonin as a Regulator of Bone Mass Accrual: Basic and Clinical
    Gerard Karsenty; Fiscal Year: 2013
  4. BONE CELL REGULATION OF THE VITAMIN D RECEPTOR GENE
    J Wesley Pike; Fiscal Year: 2013
  5. Mineralization of the matrix in disease and health
    PETER S ROWE; Fiscal Year: 2013
  6. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
  7. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
  8. A New Regulator of Trabecular Bone Formation
    Edward C Hsiao; Fiscal Year: 2013
  9. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
  10. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013

Detail Information

Publications16

  1. ncbi Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein
    Hong Chen
    Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute, Cedars Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA
    J Biol Chem 281:39114-20. 2006
    ..In particular, chromatin immunoprecipitation data suggest that, in addition to its RNA-processing functions, hnRNP C1/C2 may be a key determinant of the temporal patterns of VDRE occupancy...
  2. pmc Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts
    Thomas S Lisse
    Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, CA, USA
    J Bone Miner Res 28:1478-88. 2013
    ..These data show for the first time that the effects of 1,25D on human bone cells are not restricted to classical VDR-mediated transcriptional responses but also involve miRNA-directed posttranscriptional mechanisms...
  3. pmc A new regulator of osteoclastogenesis: estrogen response element-binding protein in bone
    Hong Chen
    Veterans Administration Medical Center and Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
    J Bone Miner Res 26:2537-47. 2011
    ..We hypothesize that ERE-BP may play a critical role in the regulation of bone homeostasis as a modulator of estrogen sensitivity as well as by direct action on the transcription of critical osteoclastogenic genes...
  4. pmc Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling
    Thomas S Lisse
    Department of Orthopaedic Surgery and Molecular Biology Institute, David Geffen School of Medicine at UCLA, 615 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Steroids 76:331-9. 2011
    ..In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements...
  5. pmc Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling
    Thomas S Lisse
    Orthopaedic Hospital Research Center, University of California Los Angeles, 615 Charles E Young Dr, South Los Angeles, CA 90095, USA
    FASEB J 25:937-47. 2011
    ..DDIT4, an inhibitor of mTOR signaling, is a direct target for 1,25(OH)(2)D(3) and VDRE-BP, and functions to suppress cell proliferation in response to vitamin D...
  6. pmc Update in vitamin D
    John S Adams
    UCLA Orthopaedic Hospital Research Center, 615 Charles Young Drive South, Room 410E, Los Angeles, California 90095 7358, USA
    J Clin Endocrinol Metab 95:471-8. 2010
    ....
  7. pmc Vitamin d-directed rheostatic regulation of monocyte antibacterial responses
    John S Adams
    Orthopaedic Hospital Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California at Los Angeles, 90095, USA
    J Immunol 182:4289-95. 2009
    ..These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes...
  8. pmc Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro
    Hong Chen
    Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Endocrinology 150:2429-35. 2009
    ..These data highlight the importance of ERE-BP as an attenuator of normal ERalpha signaling in vivo and further suggest that ERE-BP is a novel target for modulation by selective estrogen receptor modulators...
  9. pmc Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation
    Nancy Liu
    Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, 615 Charles E Young Drive South, Los Angeles, California 90095, USA
    Endocrinology 149:4799-808. 2008
    ..These data indicate that both local and endocrine synthesis of 1,25(OH)2D3 affect colitis in DSS-treated mice. Lack of Cyp27b1 exacerbates disease in this model, suggesting that similar effects may occur with vitamin D deficiency...
  10. pmc Back to the future: a new look at 'old' vitamin D
    Rene F Chun
    Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, 615 Charles E Young Drive South, Los Angeles, California 90095, USA
    J Endocrinol 198:261-9. 2008
    ..In the following review, we provide a fresh perspective on vitamin D signaling in non-classical target cells such as macrophages by highlighting novel factors associated with the transport and action of this pluripotent secosteroid...
  11. ncbi Substrate and enzyme trafficking as a means of regulating 1,25-dihydroxyvitamin D synthesis and action: the human innate immune response
    John S Adams
    Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    J Bone Miner Res 22:V20-4. 2007
    ..In this review, we use vitamin D-directed events in the human innate immune response to Mycobacterium tuberculosis as a physiologically relevant model system in which to highlight the importance of these intracellular traffic patterns...
  12. pmc Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity
    John S Adams
    Department of Endocrinology, Diabetes and Metabolism, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
    Nat Clin Pract Endocrinol Metab 4:80-90. 2008
    ..Specific examples of this will be detailed in the current Review, with particular emphasis on the immunomodulatory properties of vitamin D...
  13. pmc Control of estradiol-directed gene transactivation by an intracellular estrogen-binding protein and an estrogen response element-binding protein
    Hong Chen
    Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Mol Endocrinol 22:559-69. 2008
    ..This appears to involve a physical association between the two proteins to form a complex that is able to interact with both E(2) and ERalpha in cytosolic and nuclear compartments...
  14. ncbi Co-chaperone potentiation of vitamin D receptor-mediated transactivation: a role for Bcl2-associated athanogene-1 as an intracellular-binding protein for 1,25-dihydroxyvitamin D3
    R F Chun
    Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Mol Endocrinol 39:81-9. 2007
    ....
  15. pmc Vitamin D and microRNAs in bone
    Thomas S Lisse
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, 50 Blossom St, Thier 11, Boston, MA 02114, USA
    Crit Rev Eukaryot Gene Expr 23:195-214. 2013
    ..The current review details our understanding of vitamin D and miRNAs with specific emphasis on the implications of this interaction for biological responses to vitamin D in one of its classical target tissues, i.e., bone. ..

Research Grants30

  1. Sex Steroids and Runx Signaling in Bone
    Baruch Frenkel; Fiscal Year: 2013
    ..They will decipher cryptic mechanisms of action of existing SERMs, and support the rationale development of novel ones, based on their influence on Runx proteins. ..
  2. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
    ..This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease. ..
  3. Serotonin as a Regulator of Bone Mass Accrual: Basic and Clinical
    Gerard Karsenty; Fiscal Year: 2013
    ..Together our studies should provide important and novel insights in the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging. ..
  4. BONE CELL REGULATION OF THE VITAMIN D RECEPTOR GENE
    J Wesley Pike; Fiscal Year: 2013
    ..These novel studies will provide new insight into mechanisms that govern VDR gene expression and function and may provide unique therapeutic opportunity. ..
  5. Mineralization of the matrix in disease and health
    PETER S ROWE; Fiscal Year: 2013
    ..Design PHEX synthetic peptides as tools to probe the role of ASARM peptides and PHEX in health and disease. ..
  6. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  7. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  8. A New Regulator of Trabecular Bone Formation
    Edward C Hsiao; Fiscal Year: 2013
    ..At the end of this award, the results and reagents from this study will be used by the candidate to apply for an independent investigator award such as the NIH R01 grant. ..
  9. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  10. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  11. Glucocorticoids, Bone Strength and Angiogenesis
    ROBERT STEWART WEINSTEIN; Fiscal Year: 2013
    ..The proposed studies aimed at the mechanisms of the loss of bone strength in GIO should provide new insights that are sorely needed and immediately vital to veterans health care. ..
  12. INTERACTION OF THE ESTROGEN RECEPTOR WITH DNA
    ANN NARDULLI; Fiscal Year: 2013
    ..Our studies will provide critical new information about the role of a variety of estrogens and progestins in the brain and aid in the design of more effective hormonal treatments for women of all ages. ..
  13. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  14. Nuclear Events in PTH Action on Bone
    Nicola C Partridge; Fiscal Year: 2013
    ..Moreover, it will define how HDACs contribute to this. In so doing, the data will also provide new perspectives into treatment of disorders of calcium metabolism, cancer-associated bone disease and other bone disorders. ..
  15. DETECTION AND MODELS OF TOXICANT EXPOSURE
    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..
  16. MAP KINASE REGULATION OF OSTEOBLAST FUNCTION
    RENNY THEODORE FRANCESCHI; Fiscal Year: 2013
    ..This may have applications for diagnosis of osteoporosis and other bone disorders, such as osteoarthritis and certain cancers. ..
  17. MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSIS
    Stavros C Manolagas; Fiscal Year: 2013
    ....
  18. The Aging Pituitary-Gonadal Axis
    George R Bousfield; Fiscal Year: 2013
    ..While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes. ..
  19. Regulation of anti-endocrine resistance of breast cancer by a network of non-codi
    Peter Kabos; Fiscal Year: 2013
    ..Data from these studies is hoped to contribute to a better understanding of the role of small RNAs in hormone responsiveness and resistance of breast cancer and ultimately to novel diagnostics and therapeutics. ..