Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disr

Posted on 2005-07-19 11:00:50 in Drug Trends |
The risks of cancer and other degenerative diseases caused by reactive oxygen species and electrophiles can be reduced by the up-regulation of detoxifying enzymes. A major mechanism whereby these protective enzymes are induced occurs through activation of the antioxidant response element (ARE) by the oxidative-stress sensor protein Kelch-like ECH-associated protein 1 (Keap1) and the transcription factor NF-E2-related factor 2 (Nrf2). Under basal conditions, Keap1 sequesters Nrf2 in the cytoplasm by binding to its Neh2 domain. Chemical inducers such as sulforaphane are known to react with Keap1 cysteine residues, thereby promoting Nrf2 nuclear accumulation and hence ARE activation. A widely accepted model for Nrf2 nuclear accumulation is that modification of Keap1 cysteines leads directly to dissociation of the Keap1-Nrf2 complex. This model is based on studies with mouse proteins and has served as the experimental basis and hypothesis for numerous investigations. Through a combination of chemical, mass spectrometry, and isothermal titration calorimetry methods, we have tested the direct-dissociation model using a series of ARE inducers: sulforaphane, isoliquiritigenin, 15-deoxy-Delta12,14-prostaglandin-J2, menadione, 1-Cl-2,4-dinitrobenzene, and biotinylated iodoacetamide. Surprisingly, these data suggest that the direct disruption model for Keap1-Nrf2 is incorrect. The relative reactivity of human Keap1 cysteines was determined. In addition to the same five cysteines identified for mouse Keap1, two highly reactive and previously unobserved cysteines were identified. Based on these results, a model is proposed that should aid in the understanding of Keap1-Nrf2 signaling mechanisms.

Read Full Story

Health Headlines

Tests Pinpoint Dementia Onset
Language and memory tests can reliably predict when a healthy elderly person is likely to develop mild cognitive impairment, a precursor to dementia
Investigating A Causal Link Between Gut Bacteria and Breast Cancer
Rush University Medical Center (USA) embarks on a research study to ascertain how microbial imbalances may impact diseases such as breast cancer.
Walnuts Improve Blood Markers of Diabetes
Yale University researchers report improved function of the blood vessel lining and reduced cholesterol levels in diabetics who consume walnuts daily.
Exercise Slashes Odds of Early Death from Heart Disease
Routine moderate exercise can reduce the risk of premature death in people with heart problems by up to 60%.
Common Sweetener Raises Blood Pressure
Added as a sweetener to many processed foods and beverages, fructose (also known as high fructose corn syrup), may increase blood pressure.
Skip the Salt and Diet Soda to Save Your Kidneys
Diets high in sodium and artificially sweetened soda linked to kidney function decline.
Antioxidants May Combat Influenza Virus
Antioxidant compounds retard the ability of influenza virus to damage a key protein in lungs
Nerve Regeneration Possible in Spinal Cord Injury
Studying an animal model of spinal cord injury, UCSD researchers report successful regeneration of nerve cells even when treatment is delayed.
26 Million Americans Have Diabetes
Gallup Survey finds that 11.3% of American adults have diabetes, and the trend upwards is projected to continue unless aggressive interventions are implemented.
The American Sleep Crisis
More than 11% of American adults surveyed say they failed to enjoy a day in the previous month where they got enough sleep.
Looking for an Anti-aging Doctor?

upcoming Events

U.S. Events
congresses
Las Vegas
fellowships
fellowships
symposium
workshops
  • Advanced Hormone Symposium
    Chicago, IL | Oct. 8-10, 2010

VIDEO: Bio-Identical Hormone
          Replacement

Dr. Sangeeta Pati, one of the world’s foremost educators and practicing physicians in the field of HRT shared “The Nuts and Bolts of Hormone Restoration” via webinar. View the Webinar.

International Events
See all events »