Michiko N. Fukuda earned her PhD in biochemistry at the University of Tokyo in 1980. She did postdoctoral work at Fred Hutchinson Cancer Research Center in Seattle prior to her recruitment to Sanford-Burnham Medical Research Institute in 1982.
1980: PhD, University of Tokyo, Biochemistry
1970: MS, University of Tokyo, Biochemistry
1968: BS, Tokyo University of Education, Botany
Related Disease
Breast Cancer, Cancer, Congenital Disorders of Glycosylation, Endometriosis, Glycosylation-Related Disorders, Inherited Disorders, Ovarian Cancer, Prostate Cancer, Testicular Cancer
Chemotherapy effectiveness is often limited by drug toxicity in healthy tissues, although methods that spare normal cells by delivering drugs specifically to tumors may help to overcome this constraint. We have identified a promising tumor-targeted drug delivery vehicle known as the IF7 peptide. Using in vitro assays, we found that the IF7 peptide bound to the protein annexin 1 (Anxa1), which is known from previous studies by others to be enriched on the surface of tumor vasculature in several tumor types. When we injected a fluorescently labeled IF7 peptide into mice with tumors, fluorescent signals appeared in the tumors within one minute of injection. By contrast the tumors showed no fluorescence when mice were pre-injected with anti-Anxa1 antibodies that inhibits IF7-Anxa1 binding, suggesting that the peptide targets tumor by homing to Anxa1. When IF7 peptide was conjugated with potent anti-cancer drug SN-38 and IF7-SN38 conjugate was injected intravenously to mice with tumors, IF7 could deliver SN-38 to tumors. We found that daily injections of an IF7-SN38 conjugate reduced a large tumor in the mouse without apparent side effects, whereas non-homing peptide-SN38 conjugate or with SN-38 alone did not reduce the tumors (Hatakeyama et al, 2011). The findings suggest that IF7 peptide may represent a clinically relevant vehicle for anti-cancer drugs.
Effect of IF7-conjugated anti-cancer drug SN-38 on colon cancer mouse model. Activa cancer cells in a large tumor produce chemiluminescence which is captured by imaging. (Hatakeyama et al, 2011).
Invasion of the trophoblast into the endometrium, an essential element of embryo implantation, resembles invasion of malignant tumors. At the initial phase of implantation, the trophoblast and the uterine epithelium establish their first contact via their respective apical cell membranes. We have identified new molecules, trophinin, tastin, and bystin that mediate cell adhesion between trophoblastic cells and endometrial epithelial cells at the respective apical cell membranes. Trophinin is an intrinsic membrane protein, and tastin and bystin are cytoplasmic proteins. All of these molecules are strongly expressed in cells involved in embryo implantation in humans. However, trophinin is not expressed in human endometrial epithelia throughout the hormonal cycle, except only those cells located close to the implanting blastocyst. Trophinin expression by endometrial epithelia is induced by human chorionic gonadotrophin (hCG) derived from the implanting embryo (Sugihara et al, 2008). While embryos invade maternal cells (Sugihara et al, 2007), maternal tissue accepts embryos. We asked what happens in the maternal epithelia when trophinin-mediated adhesion takes place, and found that trophinin-mediated cell adhesion triggers an apoptotic signal in maternal epithelial cells (Tamura et al, 2011).
Distinct signal transduction of trophinin-mediated cell adhesion in trophectoderm cell and endometrial epithelial cells. In trophoblastic cells, ErbB4 (receptor tyrosine kinase) is arrested by bystin/trophinin complex. When trophinin-mediated cell adhesion takes palce, ErbB4 is released from bystin. This allows ErbB4 to be activated by phosphorylation. In endometrial epithelial cells, trophinin-mediated cell adhesion releases PKCd from trophinin. PKCd was then translocated to the nucleus, where it activates caspase 3 for apoptosis (Tamura et al., 2011).
Hatakeyama S, Sugihara K, Shibata TK, Nakayama J, Akama TO, Tamura N, Wong SM, Bobkov AA, Takano Y, Ohyama C, Fukuda M, Fukuda MN (2011) Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide. Proc Natl Acad Sci U S A 108: 19587-19592
Sugihara K, Kabir-Salmani M, Byrne J, Wolf DP, Lessey B, Iwashita M, Aoki D, Nakayama J, Fukuda MN (2008) Induction of trophinin in human endometrial surface epithelia by CGbeta and IL-1beta. FEBS Lett 582: 197-202
Sugihara K, Sugiyama D, Byrne J, Wolf DP, Lowitz KP, Kobayashi Y, Kabir-Salmani M, Nadano D, Aoki D, Nozawa S, Nakayama J, Mustelin T, Ruoslahti E, Yamaguchi N, Fukuda MN (2007) Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation. Proc Natl Acad Sci U S A 104: 3799-3804
Tamura N, Sugihara K, Akama TO, Fukuda MN (2011) Trophinin-mediated cell adhesion induces apoptosis of human endometrial epithelial cells through PKC-delta. Cell Cycle 10 : 135-143
Tamura N, Sugihara K, Akama TO, Fukuda MN
Cell Cycle 2011 Jan 1 ;10(1):135-43Hatakeyama S, Sugihara K, Nakayama J, Akama TO, Wong SM, Kawashima H, Zhang J, Smith DF, Ohyama C, Fukuda M, Fukuda MN
Proc Natl Acad Sci U S A 2009 Mar 3 ;106(9):3095-100Hatakeyama S, Sugihara K, Lee SH, Nadano D, Nakayama J, Ohyama C, Fukuda MN
J Urol 2008 Aug ;180(2):767-71Dr. Carl F. Ware received his PhD in Molecular Biology and Biochemistry from the University of California, Irvine in 1979. From 1979-81, while supported by a prestigious National Research Service Award from the NIH, Dr. Ware conducted research at the University of Texas Health Science Center in San Antonio in membrane biochemistry and the complement system with Dr. W. Kolb. In 1981, Dr. Ware joined the research groups of Dr. Jack Strominger and Dr. Tim Springer at Dana-Farber Cancer Institute, Harvard Medical School, where he developed monoclonal antibodies to discover several membrane proteins associated with T cell function. Dr. Ware established his research laboratory in 1982, as an Assistant Professor of Immunology in the Biomedical Sciences Program at the University of California, Riverside, advancing to full professor before joining the La Jolla Institute for Allergy and Immunology in 1996 as Head of the Division of Molecular Immunology. Dr. Ware also holds a joint appointment in the Department of Biology at the University of California, San Diego. In 2010, Dr. Ware was recruited to Sanford Burnham Prebys as Director of the Infectious and Inflammatory Diseases Center, where he continues his research in molecular immunology and virology. Dr. Ware also advises several biotechnology companies on approaches to drug development and most recently, he founded CoSignaling Pathway Research, Inc., to help translate his discoveries into new therapies for cancer, infectious and autoimmune diseases.
Related Disease
Arthritis, Breast Cancer, Cancer, Crohn’s Disease (Colitis), Infectious Diseases, Inflammatory Bowel Disease, Inflammatory/Autoimmune Disease, Inherited Disorders, Leukemia/Lymphoma, Myeloma, Pathogen Invasion, Psoriasis, Systemic Lupus Erythematosus, Type 1 Diabetes
Techniques and Technologies
Transplantation
Research in the Laboratory of Molecular Immunology is directed at defining the intercellular communication pathways controlling immune responses. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines in regulating decisions of cell survival and death, especially in responses to viral pathogens. Translational research is redirecting the communication networks of TNF superfamily to alter the course of autoimmune and infectious disease and cancer.
The laboratory’s work has lead to the discovery of several members of TNF cytokine superfamily and their signaling circuitry. The importance of the signaling circuitry of the immediate family of TNF related cytokines is apparent in the diversity of physiological systems dependent upon their function. TNF, LTαβ and LIGHT modulate lymphoid organ development, homeostasis, and architecture representing cellular interactions between lymphocytes, antigen presenting cells and surrounding stromal cells. These cellular interactions initiate effective host defenses to viral pathogens. Moreover, our studies on modulation the TNF/LT related cytokines by viruses is revealing novel targets for intervention in autoimmune diseases.
The Lymphotoxin-αβ and LIGHT cytokine systems, along with TNF, form an integrated cytokine-signaling circuit that regulates the development and homeostasis of the innate and adaptive immune systems (Fig. 1). The TNF related cytokines assemble as trimers and cluster their specific cell surface receptors to initiate signaling. Both TNF and LTα bind two TNF receptors (TNFR) type 1 and 2. LTα forms a heterotrimer with membrane anchored LTβ creating a ligand with distinct receptor specificity. In contrast with LTα, the LTα1β2 heterotrimer signals exclusively via the LTβ receptor (LTβR), which is expressed on stromal and myeloid cells. LTβR is also activated by another ligand, LIGHT, which binds to the herpesvirus entry mediator (HVEM). A viral ligand, the envelope glycoprotein D of Herpes Simplex virus also binds to HVEM. The signaling pathways activated by these receptors show commonality, yet distinctions exist that reveal each pathway’s unique contribution to cellular differentiation. A goal of the laboratory is to develop a full understanding of the integrated physiological functions of these cytokines in disease pathogenesis. Targeting TNF aids in controlling inflammation in some but not all autoimmune diseases, thus, elucidating the fundamental properties of these communication circuits may provide new opportunities in the clinic.
Fig. 1 Integrated circuits: TNF/LT related cytokines. TNF, LTβ and LIGHT are type 2 membrane proteins that assembled as trimers that engage transmembrane receptors with a characteristic cysteine-rich domain. This family shows significant cross-usage of ligands and receptors (binding specificity is indicated by arrows). LIGHT is a paralog of LTβ; HVEM, herpesvirus entry mediator; DcR3, decoy receptors 3 also binds Fas Ligand and TL1A (not shown). TNFR1 contains a death signaling domain, whereas TNFR2, LTβR and HVEM contain a peptide interaction motif for the TRAF adaptors.
The NFkB inducing kinase (NIK) is the key molecule that controls the non-canonical pathway of NFkB activation by several members of the TNF receptor superfamily through direct binding of the TRAF adaptors. In unstimulated cells, constitutive proteosome degradation prevents NIK from accumulation. Degradation of NIK is mediated by a cytosolic ubiquitin E3 ligase comprised of TNFR-associated factors (TRAF), a family of Zinc RING finger proteins. The ubiquitin:NIK E3 ligase is a multisubunit complex comprised of TRAF3 and TRAF2 in association with the cellular inhibitors of apoptosis (cIAP)-1 and 2. In the complex, TRAF3 binds NIK, and TRAF2 engages cIAP. All three subunits contain RING and Zn finger motifs that are required for ubiquitin E3 ligase activity and NIK turnover. This highly efficient ubiquitin:NIK E3 ligase maintains NIK at vanishing low levels, below detection by the most sensitive assays. Thus, TRAF3 and TRAF2 function as inhibitors of NIK suppressing NFkB activation.
The trimeric ligands of the TNF superfamily initiate signaling by clustering of their cognate receptors; however, the translation of receptor ligation to the activation of intracellular signals is unknown. TRAF3 and TRAF2 directly associate with LTβR and other receptors rapidly after ligand binding, implicating their role in signaling. Our work revealed that the TRAF3 binding site for NIK is located in the common receptor-binding crevice, thus the recruitment of TRAF3 to the ligated LTβR directly competes with NIK for TRAF3 (Fig.2). Similarly, recruitment of TRAF2 to the LTβR displaced cIAP from TRAF2. Furthermore, TRAF2 and TRAF3 recruited to the LTbR cytosolic domain were polyubiquitinated and degraded. Polyubiquitination and degradation of TRAF3 and TRAF2 was dependent on the TRAF2 RING domain. NIK liberated from its association with TRAF3 engaged IKKα propagating the serine kinase cascade leading to the formation of the active NF-kB p52/RelB transcriptional complex. Together, these results indicate the LTβR serves as an allosteric regulator by competitively displacing the substrate NIK and redirecting the specificity of the ubiquitin:NIK E3 ligase to ubiquitinate the TRAF molecules.
Fig. 2 Allosteric regulation of ubiquitin:NIK and TRAF3 E3 ligase by the LTβR. NIK is maintained at low levels in non-stimulated cells by Ub-dependent degradation via Ubiquitin:NIK E3 ligase consisting of TRAF3-TRAF2-cIAP complex. Ligation of LTβR recruits TRAF3 and TRAF2, with binding in the TRAF crevice, where NIK and cIAP also bind. LTβR competitively displaces NIK and cIAP, which halts the ubiquitinylation of NIK. F474 in TRAF3, and F410 in TRAF2 define the key binding sites for LTβR, NIK and cIAP. The specificity of the ubiquitin ligase is redirected to TRAF3 and TRAF2 when bound to the LTβR, forming a ubiquitin:TRAF E3 ligase that catalyzes polyubiquitination of TRAF2 and TRAF3. Consequentially, TRAF3 and TRAF2 are rapidly degraded depleting the cellular pools of TRAF3 and TRAF2, and allowing ligated LTβR to bind more TRAF3. Liberated NIK binds IKKα promoting p100 processing, essential for the formation of the RelB/p52 transcription complex
The functional role of LIGHT-HVEM in immune physiology has emerged as a potent activation signal for T cells. For instance, mice that constitutively expressed LIGHT in T cells developed a profound intestinal inflammation with expansion of activated T and B cells reminiscent of inflammatory bowel disease (IBD), an intestinal autoimmune condition with multigenic inheritance patterns. Recent identification of a genetic susceptibility locus for human inflammatory bowel disease at chromosome 19p13.3 revealed LIGHT as a candidate, although this chromosomal region is gene dense with several interesting candidates. Polymorphic variants in LIGHT impact in opposite fashion binding to LTβR and DcR3. These polymorphisms may represent natural selections in attempts to achieve balance between homeostasis and the inflammation and tissue damage needed for effective host defenses. These findings provide additional clues to the role of LIGHT in IBD.
Another distinct role for HVEM was revealed as an activator of an inhibitory cosignaling molecule, B T lymphocyte attenuator (BTLA). This finding represents the first example of a TNFR interacting with an Ig family member. HVEM appears to serve as a molecular switch between proinflammatory and inhibitory cosignaling for the activation of T cells.
Fig. 3 The LIGHT-HVEM-BTLA system. LIGHT is a positive regulator of HVEM signaling via TRAFs leading to activation of NFkB and AP1. HVEM activates inhibitory signaling by inducing tyrosine phosphorylation of the ITIM motif in BTLA. Decoy receptor-3 binds LIGHT inhibiting HVEM signaling; gD of herpes simplex virus binds HVEM blocking LIGHT and BTLA binding; UL144 of HCMV binds BTLA.
Herpesviruses are adept at modifying host immune responses. These pathogens persist in the host despite strong immune responses. The large DNA genomes of herpesviruses encode a variety of immune modulators, many of which have unknown functions. TNF signaling pathways regulate cell survival and death providing strong selective pressure for pathogens to evolve specific evasion mechanisms. Targeting members of the TNF/LT superfamily of cytokines is a strategy found in all herpesvirus, which suggests the existence of an intimate evolutionary link in their host-parasite relationship. We are interested in exploiting this evolutionary knowledge to learn how to control the immune system without causing immune suppression. Our recent studies indicate that evolutionary divergent herpesviruses target the LIGHT-HVEM-BTLA system (Fig. 3) providing strong evidence that this pathway is important for the T cell functions.
This intimate relationship between herpesvirus and the TNF-related cytokines led to the discovery of a novel mechanism of virus suppression by our laboratory. The experiments revealed the ability of LT-related cytokines to mediate a non-apoptotic block of viral replication that requires NFkB-dependent activation of interferon beta (IFNβ) gene expression. The dependence on virus and Lymphotoxin signaling to induce IFNb provides a molecular example of host-virus coexistence, which may in part account for the ability of CMV to establish a state of coexistence (détente), with its immunocompetent host. Our major goal is to use this knowledge to develop new approaches to the treatment of persistent virus infections.
Paper: Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation
Faculty Position in Immunology
Gommerman JL, Browning JL, Ware CF
Cytokine Growth Factor Rev 2014 Apr ;25(2):139-45Cheung TC, Coppieters K, Sanjo H, Oborne LM, Norris PS, Coddington A, Granger SW, Elewaut D, Ware CF
J Immunol 2010 Aug 1 ;185(3):1949-58Cheung TC, Oborne LM, Steinberg MW, Macauley MG, Fukuyama S, Sanjo H, D’Souza C, Norris PS, Pfeffer K, Murphy KM, Kronenberg M, Spear PG, Ware CF
J Immunol 2009 Dec 1 ;183(11):7286-96After receiving his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, Dr. Millán first joined the La Jolla Cancer Research Foundation (LJCRF) in 1977, the predecessor of Sanford Burnham Prebys, as a trainee in clinical enzymology. He completed his PhD studies in Medical Biochemistry at the University of Umeå, Sweden and after post-doctoral stints in Copenhagen and LJCRF he was appointed to the faculty at SBP in 1986. He served as Professor of Medical Genetics in the Department of Medical Biosciences at his alma mater, Umeå University, Sweden, from 1995-2000. He was appointed Sanford Investigator at the Sanford Children’s Health Research Center at Sanford Burnham Prebys in 2008.
2018: ASBMR Lawrence G. Raisz Award for Pre-clinical Research.
2001: Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain
1992: Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.
Member, Scientific Advisory Board, Soft Bones
Related Disease
Arthritis, Bone Mineralization Disorders, Cardiovascular Diseases, Colorectal Cancer, Crohn’s Disease (Colitis), Heart Disease, Inherited Disorders, Metabolic Syndrome, Peripheral Vascular Disease, Testicular Cancer
Phenomena or Processes
Cardiovascular Biology, Disease Therapies, Extracellular Matrix, Protein Structure-Function Relationships
Anatomical Systems and Sites
Cardiovascular System, Musculoskeletal System, Vasculature
Research Models
Mouse
The Millán laboratory works on understanding the mechanisms that control normal skeletal and dental mineralization and elucidating the pathophysiological abnormalities that lead to heritable soft bones conditions such as Hypophosphatasia (HPP) and to soft-tissue calcification, including vascular calcification, that is a hallmark in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millán’s research has already contributed to the implementation of a novel therapy for HPP, a genetic disease caused by deficiency in tissue-nonspecific alkaline phosphatase (TNAP) function, that leads to accumulation in the extracellular space of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. HPP is characterized by defective mineralization of bones (rickets or osteomalacia), and teeth that display a lack of acellular cementum, hypomineralized dentin and enamel, and periodontal defects. Dr. Millán’s team has demonstrated the effectiveness of enzyme replacement therapy using mineral-targeted recombinant TNAP (asfotase alfa) to prevent the skeletal and dental defects in the TNAP knockout mouse model of infantile HPP. This therapy was approved in 2015 for the treatment of patients with pediatric-onset HPP.
Current efforts, in collaboration with Professor Miyake’s group in Japan (https://www.nms-gt.org/en/members), focus on developing gene therapy as an alternative approach to treat HPP. Dr. Millán’s group has also identified key pathophysiological changes that lead to calcification of the arteries in animal models of generalized arterial calcification of infancy, pseudoxanthoma elasticum and related genetic diseases as well as in animal models of chronic kidney disease. His group, in collaboration with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys, has developed proprietary compounds able to ameliorate the soft-tissue calcification in these conditions and clinical trials are now underway using these first-in-class small molecule inhibitors.
Kinoshita Y, Mohamed FF, Amadeu de Oliveira F, Narisawa S, Miyake K, Foster BL, Millán JL
J Bone Miner Res 2021 Sep ;36(9):1835-1849Rolf Bodmer earned his PhD in Biochemistry and Neurobiology from the University of Basel, Switzerland, in 1983. Dr. Bodmer trained as a postdoctoral fellow in Neurobiology at the Albert Einstein College of Medicine in New York, and also studied Molecular Genetics at the University of California, San Francisco. He was appointed Assistant Professor of Biology in 1990 at the University of Michigan. There, he was promoted to Associate Professor of Biology in 1996, and then appointed to Associate Professor of Molecular, Cellular and Developmental Biology in 2001. Dr. Bodmer joined Sanford Burnham Prebys in 2003, where he is Professor and Program Director of the Development, Aging, and Regeneration Program.
Adjunct professor, University of California, San Diego
1 P01 AG033561 “Genetic Analysis of Drosophila Functional Aging”
Ellison Foundation Senior Scholar Award
Related Disease
Cancer, Cardiovascular Diseases, Heart Disease, Inherited Disorders, Metabolic Diseases, Metabolic Syndrome, Muscular Dystrophy, Neurodegenerative and Neuromuscular Diseases, Obesity, Parkinson’s Disease
The Bodmer Laboratory is interested in the molecular mechanisms of organ formation, how patterns are generated and how cells and tissue types assume their correct fates and functions. The Bodmer lab is pursuing this interest by studying the genetic functions and interactions that specify heart development and maintain heart performance in the Drosophila model, in the hope of elucidating basic principles in organogenesis and functionality.
Mesoderm
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Cardiac Mesoderm
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Cardiac Cell Types
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Morphogenesis
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Heart Function
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Aging Heart
We study the HIF and Notch pathways in various organismal responses to hypoxia. Both of these pathways as well as mechanisms and responses to hypoxia are of high relevance to cancer research.
We are also studying master regulatory networks in how they control metabolism and obesity. These fundamental studies on obesity pathways will also be highly relevant to cancer metabolism.
Neely GG, Kuba K, Cammarato A, Isobe K, Amann S, Zhang L, Murata M, Elmén L, Gupta V, Arora S, Sarangi R, Dan D, Fujisawa S, Usami T, Xia CP, Keene AC, Alayari NN, Yamakawa H, Elling U, Berger C, Novatchkova M, Koglgruber R, Fukuda K, Nishina H, Isobe M, Pospisilik JA, Imai Y, Pfeufer A, Hicks AA, Pramstaller PP, Subramaniam S, Kimura A, Ocorr K, Bodmer R, Penninger JM
Cell 2010 Apr 2 ;141(1):142-53
