KEAP1-NRF2 System Regulating Oxidative Stress Response
Our body has ability to sense environmental insults, including oxidative stress, and activate cellular defense enzymes. Transcription factor NRF2 is essential for the coordinated induction of cellular defense enzymes and protection of tissues. Nrf2-null mice are sensitive to a wide variety of toxic electrophiles and reactive oxygen species (ROS). KEAP1 acts as a subunit of ubiquitin-E3 ligase and degrades Nrf2 constitutively, and also acts as a sensor for oxidative and electrophilic stresses. We have verified the Cysteine Code and Hinge-and- Latch model through structure biology, mouse genetics, and human disease analyses, and these analyses provide solid basis for the development of drugs that induce NRF2. In fact, NRF2 inducers are now actively developed for kidney diseases and neurodegenerative disorders. Meanwhile, many somatic missense mutations have been identified in KEAP1 and NRF2 genes of human cancers. These mutations disrupt the KEAP1-NRF2 complex and result in constitutive activation of NRF2, and elevated expression of NRF2 target genes confers advantages on the growth of cancer cells through the metabolic reprogramming and induction of cellular defense enzymes. The Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.
Genetic Diagnosis of Human Disease by WGS: Basis of Precision Medicine
The aim of our Precision Medicine Program is to leverage the research capacity established by the 5+2 Flagship Plan, which is centered around whole genome sequencing (WGS). We have been channeling the WGS and bioinformatics capabilities of our team in order to pilot the adoption of clinical projects in areas such as rare diseases, targeted cancer treatment, the identification of potential non-cancer chronic diseases in individuals and preventive medicine; these related themes are expected to be used to drive the development of the precision medicine industry in Taiwan. Over the past year, we have analyzed over one hundred families affected with rare or undiagnosed diseases, including those of immunodeficiency, epilepsy, spinocerebellar ataxia, hearing impairment, and developmental delay and intellectual deficit. Overall, we have provided definitive genetic diagnosis for over 60% of the cases, a significant of them were previously undiagnosed. Lately, we have been extending our WGS-based research to cancer genomics to characterize the genomic landscapes of different subtypes of liver cancer and urothelial cancer. Our so-far experiences working with clinicians/researchers in different medical centers in Taiwan have been most rewarding in providing definitive answers and new insights for difficult cases to the doctors, the patients, and the family members. In this conference, we hope to report to you some of the findings that were previously unaware of, without taking a whole genome sequencing approach.
Dr. Shu-Li (Julie) Wang, NHRI
Dr. Pao-Lin Kuo, National Cheng Kung University Hospital