Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Upcoming)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact

Review Series

Korsmeyer Award 25th Anniversary Collection

The Stanley J. Korsmeyer Award recognizes the outstanding achievements of ASCI members in advancing knowledge in a specific field and in mentoring future generations of life science researchers. The recognition, which was first known as the ASCI Award, was renamed in 2006 in honor of Dr. Stanley J. Korsmeyer, a dedicated and accomplished physician-scientist and mentor who was the first recipient in 1998 and who passed away in 2005. 2023 marks the 25th Anniversary of the Korsmeyer Award, and the ASCI and JCI commemorate this milestone with a collection of articles contributed by the award's past winners. Articles will be added to this collection throughout the year.

Articles in series

Hypoxia-inducible factors: cancer progression and clinical translation
Elizabeth E. Wicks, Gregg L. Semenza
Elizabeth E. Wicks, Gregg L. Semenza
Published June 1, 2022
Citation Information: J Clin Invest. 2022;132(11):e159839. https://doi.org/10.1172/JCI159839.
View: Text | PDF

Hypoxia-inducible factors: cancer progression and clinical translation

  • Text
  • PDF
Abstract

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.

Authors

Elizabeth E. Wicks, Gregg L. Semenza

×

Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer
William G. Kaelin Jr.
William G. Kaelin Jr.
Published September 15, 2022
Citation Information: J Clin Invest. 2022;132(18):e162480. https://doi.org/10.1172/JCI162480.
View: Text | PDF

Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer

  • Text
  • PDF
Abstract

Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.

Authors

William G. Kaelin Jr.

×

Targeting ryanodine receptors to treat human diseases
Andrew R. Marks
Andrew R. Marks
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e162891. https://doi.org/10.1172/JCI162891.
View: Text | PDF

Targeting ryanodine receptors to treat human diseases

  • Text
  • PDF
Abstract

This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger in all living organisms. From C. elegans to mammals, Ca2+ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca2+ overload can result in loss of function and death. Intracellular Ca2+ release channels evolved to safely provide large, rapid Ca2+ signals without exposure to toxic extracellular Ca2+. RyRs are intracellular Ca2+ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR-mediated intracellular Ca2+ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer’s disease, posttraumatic stress disorder, and Huntington’s disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.

Authors

Andrew R. Marks

×

Cargo selection in endoplasmic reticulum–to–Golgi transport and relevant diseases
Vi T. Tang, David Ginsburg
Vi T. Tang, David Ginsburg
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e163838. https://doi.org/10.1172/JCI163838.
View: Text | PDF

Cargo selection in endoplasmic reticulum–to–Golgi transport and relevant diseases

  • Text
  • PDF
Abstract

Most proteins destined for the extracellular space or various intracellular compartments must traverse the intracellular secretory pathway. The first step is the recruitment and transport of cargoes from the endoplasmic reticulum (ER) lumen to the Golgi apparatus by coat protein complex II (COPII), consisting of five core proteins. Additional ER transmembrane proteins that aid cargo recruitment are referred to as cargo receptors. Gene duplication events have resulted in multiple COPII paralogs present in the mammalian genome. Here, we review the functions of each COPII protein, human disorders associated with each paralog, and evidence for functional conservation between paralogs. We also provide a summary of current knowledge regarding two prototypical cargo receptors in mammals, LMAN1 and SURF4, and their roles in human health and disease.

Authors

Vi T. Tang, David Ginsburg

×

Entry receptors — the gateway to alphavirus infection
Ofer Zimmerman, … , Lucas J. Adams, Michael S. Diamond
Ofer Zimmerman, … , Lucas J. Adams, Michael S. Diamond
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e165307. https://doi.org/10.1172/JCI165307.
View: Text | PDF

Entry receptors — the gateway to alphavirus infection

  • Text
  • PDF
Abstract

Alphaviruses are enveloped, insect-transmitted, positive-sense RNA viruses that infect humans and other animals and cause a range of clinical manifestations, including arthritis, musculoskeletal disease, meningitis, encephalitis, and death. Over the past four years, aided by CRISPR/Cas9–based genetic screening approaches, intensive research efforts have focused on identifying entry receptors for alphaviruses to better understand the basis for cellular and species tropism. Herein, we review approaches to alphavirus receptor identification and how these were used for discovery. The identification of new receptors advances our understanding of viral pathogenesis, tropism, and evolution and is expected to contribute to the development of novel strategies for prevention and treatment of alphavirus infection.

Authors

Ofer Zimmerman, Autumn C. Holmes, Natasha M. Kafai, Lucas J. Adams, Michael S. Diamond

×

Tugs-of-war in science
Mitchell A. Lazar
Mitchell A. Lazar
Published October 17, 2022
Citation Information: J Clin Invest. 2022;132(20):e165312. https://doi.org/10.1172/JCI165312.
View: Text | PDF

Tugs-of-war in science

  • Text
  • PDF
Abstract

Authors

Mitchell A. Lazar

×

Lessons learned: from mentored to mentor
Joseph Heitman
Joseph Heitman
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e167444. https://doi.org/10.1172/JCI167444.
View: Text | PDF

Lessons learned: from mentored to mentor

  • Text
  • PDF
Abstract

This Viewpoint was written in association with the 25th anniversary of the American Society for Clinical Investigation’s (ASCI’s) Stanley J. Korsmeyer Award, which honors the highest standards of scientific excellence, meritorious research, intellectual integrity, and the mentoring of future life-science researchers. In 2018, the award recognized Joseph Heitman (Figure 1), for his key contributions to our understanding of how eukaryotic microbial pathogens evolve, cause disease, and develop drug resistance and his discovery of TOR and FKBP12 as targets of the immunosuppressive chemotherapeutic drug rapamycin. Dr. Heitman has mentored numerous undergraduates, medical students, graduate students, and postdoctoral and medical fellows, many of whom have developed independent careers in medicine and basic biomedical research.

Authors

Joseph Heitman

×

Advertisement

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts