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Leukemia (1999) 13, 1109–1166

 1999 Stockton Press All rights reserved 0887-6924/ 99 $12.00

http:/ / www.stockton-press.co.uk/ leu

REVIEW Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs

  • WL Blalock1, C Weinstein-Oppenheimer1,2, F Chang1, PE Hoyle1, X-Y Wang3, PA Algate4, RA Franklin1,5, SM Oberhaus1,5
  • ,

LS Steelman1 and JA McCubrey1,5

1Department of Microbiology and Immunology, 5Leo Jenkins Cancer Center, East Carolina University School of Medicine Greenville, NC, USA; 2Escuela de Qu´ımica y Farmacia, Facultad de Medicina, Universidad de Valparaiso, Valparaiso, Chile; 3Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN, USA; and 4Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Over the past decade, there has been an exponential increase

growth factor), Flt-L (the ligand for the flt2/3 receptor), erythropoietin (EPO), and others affect the growth and differentiation

in our knowledge of how cytokines regulate signal transduc- tion, cell cycle progression, differentiation and apoptosis.

of these early hematopoietic precursor cells into cells of the

Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified

myeloid, lymphoid and erythroid lineages (Table 1).1–4 This review will concentrate on IL-3 since much of the knowledge of how cytokines affect cell growth, signal transduction, and apoptosis has been elucidated from research with IL-3-dependent cell lines. Some other cytokines (eg GM-CSF and IL-5) exert their effects through similar mechanisms.

by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malig- nant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate mul- tiple receptors and be more effective in stimulating the repopu- lation of hematopoietic cells after myelosuppressive chemo- therapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cyto- kines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently exam- ined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these com- plex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the poten- tial to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

IL-3 was initially defined by its ability to induce the enzyme
20-␣-hydroxysteroid dehydrogenase in cultures of splenic lymphocytes from nude mice.5 However, it soon became apparent that IL-3 was being studied by a number of investigators under a variety of aliases. It was called persisting cellstimulating factor (PSF),6 mast cell growth factor (MCGF),7 hematopoietic cell growth factor (HCGF),8 histamine-producing cell-stimulating factor,9 multi-colony stimulating factor (multi-CSF),10 Thy-1-inducing factor,5 and burst promoting activity (BPA).11 All of these growth stimulatory activities were subsequently identified as the same protein and renamed IL-3. IL-3 was shown to act on both myeloid and lymphoid lineages by in vitro studies. In vivo administration of pharmacological doses of recombinant IL-3 to mice resulted in the increased production of red blood cells, leukocytes and platelets.12 Moreover, over-expression of the IL-3 gene in hematopoietic progenitors via retroviral transduction of bone marrow cells resulted in a non-neoplastic, myeloproliferative syndrome in vivo.13 To further understand the role of IL-3 in vivo, transgenic mice expressing antisense IL-3 RNA were created. These mice, which exhibited decreased serum levels of IL-3, developed either a B cell lymphoproliferative syndrome or a neurological dysfunction.14 In more recent studies with IL-3- deficient mice, a role for IL-3 in contact hypersensitivity was observed. IL-3 was determined to be necessary for efficient priming of hapten-specific contact hypersensitivity.15

Keywords: cytokines; signal transduction; anti-neoplastic drugs; oncogenes; apoptosis

Cytokines and hematopoiesis

Cytokines stimulate cell cycle progression, proliferation, and differentiation, as well as inhibit apoptosis of hematopoietic cells.1–3 Peripheral blood cells are generated from self-renewable, pluripotential hematopoietic stem cells in the bone
IL-3 transgenic mice have also been used to examine the effects of constitutive IL-3 expression on development and neoplasia. Recent evidence indicative of neurological dysfunction in IL-3-transgenic mice supports the idea that this hematopoietic cytokine performs key roles in the central nervous system as well.14–19 The pleiotropic roles of this cytokine must be considered when therapies are developed based upon alteration of IL-3 expression, down-regulation of cognate receptor expression and function, or destruction of IL-3 receptor (IL-3R)-positive cells by chimeric IL-3-toxin molecules.

  • marrow.
  • Cytokines
  • such
  • as
  • interleukin-3
  • (IL-3),

granulocyte/macrophage colony stimulating factor (GM-CSF), stem cell factor (SCF, or steel factor, c-Kit-L, macrophage

Correspondence: JA McCubrey, Department of Microbiology and Immunology, East Carolina University School of Medicine, Brody Building 5N98C, Greenville, NC 27858, USA; Fax: 252-816-3104 Received 2 March 1999; accepted 14 May 1999

Review

WL Blalock et al

1110

Table 1

Abbreviations of cytokines, growth factors, their receptors and cellular targets

  • Abbreviation
  • Full name
  • Target cells or function

EGF epo
Epidermal growth factor Erythropoietin
Affects the growth of many cells Erythroid cells flt-2/flt-3L G-CSF
Ligand for the flt2/flt3 receptor Early hematopoietic progenitor cells Granulocyte-colony stimulating Granulocyte/monocyte progenitor cells factor

  • GM-CSF
  • Granulocyte/macrophage-

colony stimulating factor
Many early hematopoietic precursor cells of the myeloid lineage, neutrophilic granulocytes, monocyte–macrophages, eosinophils; has the ability to activate macrophages

  • gp130
  • Glycoprotein 130
  • Signal transducing receptor protein shared among IL-6, LIF, oncoM and other

cytokines
IL-3 IL-3R IL-4 IL-5 LIF
Interleukin-3 Interleukin-3 receptor Interleukin 4 Interleukin 5 Leukemia inhibitory factor
Many early hematopoietic precursor cells of both myeloid and lymphoid lineages Present on many early hematopoietic cells B cells, mast cells, some T cells B cells, eosinophils Homology with oncoM, inhibits proliferation of tumor cell lines, affects a broad range of cells
M-CSF

oncoM SCF
Macrophage-colony stimulating Granulocyte–monocyte progenitor, receptor is the product of the c-fms protofactor Oncostatin M oncogene 28-kDa protein with homology to LIF, inhibits proliferation of tumor cell lines, affects a broad range of cells, expression induced by Jak/STAT pathway
Stem cell factor, also known as Many early hematopoietic cells, receptor is the product of the c-kit proto-oncogene, c-kit ligand stimulates proliferation of myeloid, erythroid and lymphoid progenitors Transforming growth factor-beta Often inhibits cell proliferation, wide tissue distribution Thrombopoietin Growth and differentiation factor for megakaryocytes, receptor is the c-mpl protooncogene
TGF-␤ TPO

Recombinant/chimeric cytokines and therapy

tration of daniplestim and G-CSF results in higher numbers of short-term and long-term clonogenic cells compared to sequential administration of daniplestim and G-CSF.29 In the rhesus myelosuppression model, daniplestim accelerated hematopoietic reconstitution in radiation-induced cytopenia. Daniplestim significantly reduced the nadir of neutropenia and the duration of thromocytopenia in animals with radiation-induced myelosuppression.27 Taken together, these data suggested that daniplestim may be clinically useful in patients with chemotherapy-induced myelosuppression and support the utility of combination therapy. Some of the chimeric cytokines developed by Searle include the myelopoietin (MPO) family (IL-3 and G-CSF receptor agonists), the promegapoietin (PMP) family (IL-3 and TPO receptor agonists) and the progenipoietin (ProGP) family (Flt3 and G-CSF receptor agonists). These chimeric molecules were developed based on the concept that a single molecule with bifunctional activities could provide synergy, that is an enhancement in activity that is greater than the addition of molecules with monofunctional activities.33,34 Additional enhancement in activity was achieved through circular permutation of the molecules such that the termini of the protein sequence were ‘linked’ and new termini were generated by ‘breaking’ the sequence at a new location. Such a process could relieve conformational constraints, add flexibility, result
A variety of engineered recombinant cytokines are currently under investigation for use in hematopoietic reconstitution of

  • patients
  • undergoing
  • myelosuppressive
  • chemotherapy

(Table 2).20–47 A fusion molecule containing IL-3 and GM-CSF (PIXY 321) developed by Immunex activates both the IL-3 and GM-CSF receptors.22–25 GD Searle Pharmaceuticals has developed a structurally and functionally distinct IL-3 receptor agonist (daniplestim) which binds to the IL-3 receptor with higher affinity than native IL- 3 but has reduced inflammatory effects.26–29 Daniplestim is a truncated form of hIL-3 but has complete biological activity. Daniplestim binds to the IL-3 receptor ␣/␤ complex with 20- fold greater affinity compared to native IL-3.26 Daniplestim induced cell proliferation with 10-fold greater potency than native IL-3 in the human acute myelogenous leukemia AML193 cell line. In colony-forming unit (CFU) assays using human bone marrow CD34+ cells, daniplestim demonstrated 22-fold greater potency than native IL-3.27 The in vivo utility of daniplestim was evident in the rhesus mobilization and myelosuppression models.28,29 In the rhesus mobilization model, the combination of daniplestim and G- CSF mobilized higher and sustained levels of stem cells in the peripheral blood. These studies demonstrated that coadminis-

Table 2

Abbreviations of recombinant/chimeric cytokines and drugs and their sources

  • Brief description
  • Name
  • Source

Daniplestim Leridistim
Modified IL-3 with higher affinity binding to the IL-3 receptor than unmodified IL-3 Monsanto/Searle

  • IL-3/G-CSF chimera
  • Monsanto/Searle

  • Immunex
  • PIXY-321
  • Fusion cytokine which binds both the IL-3 and GM-CSF receptors

  • Flt-3L/G-CSF chimera
  • Progenipoietin

Promegapoietin
Monsanto/Searle

  • Monsanto/Searle
  • IL-3/TPO chimera

Review

WL Blalock et al

1111

in different conformational constraints and introduce a new structure–activity relationship.33,34 In addition, permutation of a molecule with two functional entities could impart an advantage with respect to the relative positioning of the two molecules as they bind to their respective receptors. In CFU assays, MPOs demonstrate greater potency than the coaddition of native IL-3 and G-CSF.33 In rhesus myelosuppression model, MPOs have been shown to be more effective in repopulating specific hematopoietic cell compartments than a combination of native IL-3 and G-CSF.36,37 In addition, MPOs effectively mobilize CD34+ and clonogenic cells in rhesus monkeys.36–38 In phase I/II clinical trials in breast cancer or lymphoma patients, MPOs are well-tolerated mobilizing agents.39–41 PMPs support the differentiation of progenitors along the megakaryocytic lineage and induces expansion of CD41+ cells in vitro.42–44 In rhesus myelosuppression model, PMPs significantly improve the platelet nadir and accelerates platelet recovery.45 In CFU assays, ProGPs demonstrate greater potency than coaddition of native Flt3 ligand and G-CSF suggesting a cooperativity of hematopoietic activities in a chimeric molecule.46,47 In mice and rhesus monkeys, ProGPs mobilize substantial numbers of hematopoietic stem cells into the peripheral blood.37,48 In rhesus myelosuppression model, ProGPs also support multilineage hematopoietic reconstitution.37 Interestingly, ProGPs have recently been shown to mobilize a large number of functional dendritic cells suggesting that it may also be effective in this area of immunotherapy.46,47 In summary, these chimeric cytokines represent a novel line of biotechnology, which shows significant promise in the treatment of certain leukemia patients. ases ␣ and ␤ (I-␬K␣ and I-␬K␤).55 These kinases phosphorylate I-␬B on serine residues which results in degradation of the protein and allows NF-␬B to enter the nucleus and transactivate gene expression. The I-␬ kinases are activated by NF-␬B inducing kinase (NIK) and the mitogen-activated protein kinase kinase kinase-1 (MEKK1).55
15-Deoxyspergualin (DSG), an immunosuppressive drug currently in phase I/II clinical trials may represent one approach to inhibiting NF-␬B activation. DSG inhibits the localization of heat shock protein 70 (Hsp 70) to the nucleus in response to heat stress, as well as the activation of NF- ␬B, through its interaction with Hsp70.56 Another approach to inhibiting NF-␬B activation involves introducing adenoviral vectors which overexpress I-␬B.57 This gene therapeutic approach may prove beneficial in the suppression of tumor growth. Increased levels of intracellular Ca2+ following TCR aggre-

  • gation allows calmodulin to activate calcineurin,
  • a

serine/threonine phosphatase.53 Activated calcineurin dephosphorylates the cytoplasmic (c) form of the transcription factor, NF-ATc (nuclear factor of activated T cells) enabling NF-AT to translocate to the nucleus (n). This results in the transactivation of cytokine gene expression, including IL-3 and GM- CSF whose promoters contain NF-AT binding sites.59–74 The immunosuppressive drugs cyclosporin A (CsA) and FK506 mediate their activity by inhibiting calcineurin activation, thereby preventing the dephosphorylation of NF-ATc58,74 (Table 4). An illustration of the regulation of IL-3 gene expression is presented in Figure 1. Similar mechanisms mediate the expression of IL-2, GM-CSF and other T cellderived cytokines.
In addition to stimulating proliferation and differentiation of hematopoietic cells, cytokines such as IL-3 also promote cell survival. IL-3-dependent cells undergo apoptosis after withdrawal of IL-3 for a prolonged period of time (12 to 48 h depending upon the cell type and species of origin).48,49 However, addition of IL-3 to IL-3-deprived cells can prevent apoptosis in a significant proportion of these cells.48,49 These anti-apoptotic functions of IL-3 and other important cytokines are critical concerns in therapeutic cytokine intervention, especially with patients having certain leukemias and minimal residual disease.
There are additional pathways by which activated PKC can stimulate cytokine gene expression. PKC can activate the Ras pathway by inactivating the GTPase activating protein (GAP), a negative regulator of Ras.61,68–70 Ras is a member of a large multi-gene family, which encodes small GTP-binding proteins that serve as molecular switches. Inactivation of GAP stimulates Ras activity, which results in an enhancement of activator-protein-1 (AP-1) binding activity.61,68–70 AP-1 can then stimulate cytokine gene expression, including IL-3 (Figure 2a). Interestingly, the neurofibromatosis-1 (NF1) gene, a tumor suppressor frequently lost in juvenile chronic myelogenous leukemia (CML), is functionally related to GAP.77,78 NF1 likely serves to block Ras activation, thus its loss leads to constitutive Ras activation and contributes to the generation of CML. Ras is frequently targeted by anti-neoplastic drugs including farnesyl transferase (FT) inhibitors (see below). Addition of a farnesyl group is necessary for Ras localization to the cytoplasmic membrane. Drugs, which block Ras farnesylation, are currently being developed by pharmaceutical companies for therapeutic use (eg Janssen, Merck).79

Regulation of IL-3 expression

Most hematopoietic cells do not usually synthesize the 26- kDa IL-3 protein. In those cells that do express the IL-3 gene, the gene is normally under stringent controls.50–76 In peripheral blood, activated T cells, natural killer cells, mast and some megakaryocytic cells can synthesize IL-3.50–53 For optimal IL-3 expression, T cells must be activated via the T cell receptor (TCR)/CD3 pathway, or by agents that mimic this pathway, eg the combination of PMA and calcium ionophores.50–53 When a T cell is activated, aggregation of the TCR/CD3 complex occurs (Table 3). Receptor aggregation is followed by a complex series of biochemical events leading to the activation of protein kinase C (PKC) and a rise in the concentration of intracellular Ca2+.50–68 Activated PKC can phosphorylate and inactivate the repressor protein, inhibitor ␬B (I-␬B), thus permitting I␬B to disassociate from nuclear factor-␬B (NF-␬B).54 This allows NF-␬B to assume an active form (Figure 1) which subsequently enters the nucleus and transactivates cytokine gene expression. In addition, there is a complex of proteins which phosphorylates I-␬B, the I-␬B kin-

Transcriptional regulation of IL-3 expression

The cis-acting elements of the human IL-3 promoter include two activation regions separated by an inhibitory region.59–74 These genetic elements lie within a region that extends to ෂ300 bp upstream of the transcription start site (Figure 2a). Inhibitory elements in the IL-3 promoter which suppress IL-3 transcription include a NIP (nuclear inhibitory protein) binding sequence located between bp −271 to −250.59 Figure 2 depicts some of the transcription factor binding sites involved in the regulation of IL-3 expression. Sequence motifs common to many cytokine promoters,

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    Leveraging the Bcl-2 Interactome to Kill Cancer Cells—

    Author Manuscript Published OnlineFirst on April 2, 2015; DOI: 10.1158/1078-0432.CCR-14-0959 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Molecular Pathways: Leveraging the Bcl-2 Interactome to Kill Cancer Cells— Mitochondrial Outer Membrane Permeabilization and Beyond Hetal Brahmbhatt1,2, Sina Oppermann2, Elizabeth J. Osterlund2,3, Brian Leber4, and David W. Andrews1,2,3 1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. 2Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. 3Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. 4Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Corresponding Author: David W. Andrews, Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada. M4N 3M5. Phone: 416-480-5120; Fax: 416-480-4375; E-mail: [email protected] Running Title: Bcl-2 Proteins as Chemotherapy Targets Disclosure of Potential Conflicts of Interest B. Leber reports receiving speakers bureau honoraria from AMGEN Canada, Bristol-Myers Squibb Canada, Celgene Canada, Novartis Canada, and Pfizer Canada. No potential conflicts of interest were disclosed by the other authors. Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 2, 2015; DOI: 10.1158/1078-0432.CCR-14-0959 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT The inhibition of apoptosis enables the survival and proliferation of tumors and contributes to resistance to conventional chemotherapy agents and is therefore a very promising avenue for the development of new agents that will enhance current cancer therapies.
  • Peptidomimetic Blockade of MYB in Acute Myeloid Leukemia

    Peptidomimetic Blockade of MYB in Acute Myeloid Leukemia

    bioRxiv preprint doi: https://doi.org/10.1101/222620; this version posted November 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Peptidomimetic blockade of MYB in acute myeloid leukemia 2 3 4 Kavitha Ramaswamy1,2, Lauren Forbes1,7, Gerard Minuesa1, Tatyana Gindin3, Fiona Brown1, 5 Michael Kharas1, Andrei Krivtsov4,6, Scott Armstrong2,4,6, Eric Still1, Elisa de Stanchina5, Birgit 6 Knoechel6, Richard Koche4, Alex Kentsis1,2,7* 7 8 9 1 Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA. 10 2 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 11 3 Department of Pathology and Cell Biology, Columbia University Medical Center and New York 12 Presbyterian Hospital, New York, NY, USA. 13 4 Center for Epigenetics Research, Sloan Kettering Institute, New York, NY, USA. 14 5 Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 15 USA. 16 6 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 17 7 Weill Cornell Medical College, Cornell University, New York, NY, USA. 18 19 * Correspondence should be addressed to A.K. ([email protected]). 1 bioRxiv preprint doi: https://doi.org/10.1101/222620; this version posted November 20, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 ABSTRACT 21 22 Aberrant gene expression is a hallmark of acute leukemias. However, therapeutic strategies for 23 its blockade are generally lacking, largely due to the pharmacologic challenges of drugging 24 transcription factors.
  • Signal Transduction and the Ets Family of Transcription Factors

    Signal Transduction and the Ets Family of Transcription Factors

    Oncogene (2000) 19, 6503 ± 6513 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Signal transduction and the Ets family of transcription factors John S Yordy1 and Robin C Muise-Helmericks*,1,2 1Center for Molecular and Structural Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, SC 29403, USA; 2Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina, SC 29403, USA Cellular responses to environmental stimuli are con- expression required for cellular growth, dierentiation trolled by a series of signaling cascades that transduce and survival. One group of downstream eectors of extracellular signals from ligand-activated cell surface these signaling pathways is the Ets family of transcrip- receptors to the nucleus. Although most pathways were tion factors. Ets family members can also be initially thought to be linear, it has become apparent that considered upstream eectors of signal transduction there is a dynamic interplay between signaling pathways pathways controlling the expression of a number of that result in the complex pattern of cell-type speci®c signaling components including both receptor tyrosine responses required for proliferation, dierentiation and kinases and intermediate signaling molecules. survival. One group of nuclear eectors of these The Ets family of transcription factors is de®ned by signaling pathways are the Ets family of transcription a conserved winged helix ± turn ± helix DNA binding factors, directing cytoplasmic signals to the control of domain (Papas et al., 1989; Wasylyk et al., 1993; gene expression. This family is de®ned by a highly Werner et al., 1995).
  • G-Protein ␤␥-Complex Is Crucial for Efficient Signal Amplification in Vision

    G-Protein ␤␥-Complex Is Crucial for Efficient Signal Amplification in Vision

    The Journal of Neuroscience, June 1, 2011 • 31(22):8067–8077 • 8067 Cellular/Molecular G-Protein ␤␥-Complex Is Crucial for Efficient Signal Amplification in Vision Alexander V. Kolesnikov,1 Loryn Rikimaru,2 Anne K. Hennig,1 Peter D. Lukasiewicz,1 Steven J. Fliesler,4,5,6,7 Victor I. Govardovskii,8 Vladimir J. Kefalov,1 and Oleg G. Kisselev2,3 1Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, Departments of 2Ophthalmology and 3Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, 4Research Service, Veterans Administration Western New York Healthcare System, and Departments of 5Ophthalmology (Ross Eye Institute) and 6Biochemistry, University at Buffalo/The State University of New York (SUNY), and 7SUNY Eye Institute, Buffalo, New York 14215, and 8Sechenov Institute for Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint Petersburg 194223, Russia A fundamental question of cell signaling biology is how faint external signals produce robust physiological responses. One universal mechanism relies on signal amplification via intracellular cascades mediated by heterotrimeric G-proteins. This high amplification system allows retinal rod photoreceptors to detect single photons of light. Although much is now known about the role of the ␣-subunit of the rod-specific G-protein transducin in phototransduction, the physiological function of the auxiliary ␤␥-complex in this process remains a mystery. Here, we show that elimination of the transducin ␥-subunit drastically reduces signal amplification in intact mouse rods. The consequence is a striking decline in rod visual sensitivity and severe impairment of nocturnal vision. Our findings demonstrate that transducin ␤␥-complex controls signal amplification of the rod phototransduction cascade and is critical for the ability of rod photoreceptors to function in low light conditions.
  • Brief Definitive Report ZAP- 70 Gene

    Brief Definitive Report ZAP- 70 Gene

    Brief Definitive Report Reconstitution of T Cell Receptor Signaling in ZAP-70-deficient Cells by Retroviral Transduction of the ZAP- 70 Gene By Naomi Taylor,* Kevin B. Bacon,¢ Susan Smith,* Thomas Jahn,* Theresa A. Kadlecekfl Lisa Uribe,* Donald B. Kohn,* Erwin W. Gelfand,IIArthur Weiss,~ and Kenneth Weinberg* From the *Division of Research Immunology and Bone Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California 90027; :~DNAX Research Institute, Palo Alto, California 94304; gHoward Hughes Medical Institute, Department of Medicine and of Microbiology and Immunology, University of California, San Francisco, California 94143; and IIDivision of Basic Sciences and Molecular Signal Transduction Program, Department of Pediatrics, National Jewish Centerfor Immunology and Respiratory Diseases, Denver, Colorado 80206 Summal-y A variant of severe combined lmmunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4 + cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4 + T cell lines w.ere established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13.