Scott André Oakes, MD
Research and Clinical Interests
ER Stress, Cell Suicide and Disease
All multicellular organisms have evolved mechanisms to silence or eliminate rogue cells that threaten the survival of the majority. As such, human cells are genetically programmed to actively commit “suicide” through a process called apoptosis when they become harmful, superfluous or irreversibly damaged. The final executioners in the apoptotic pathway are a family of proteins called caspases that ultimately digest the cell from the inside out. While great strides have been made in identifying the core apoptotic machinery that dismantles the cell, we still know relatively little about how the process begins. In particular, we are largely ignorant of how cells sense internal damage (say in response to chemotherapy), determine if the damage is lethal, and then relay this information to the apoptotic machinery. Various physiological events (e.g., secretory cell differentiation) and pathological conditions (e.g., hypoxia, nutrient deprivation) can overwhelm the protein folding capacity of the endoplasmic reticulum (ER). Initially, the stress placed on the ER by an abundance of misfolded protein activates an evolutionarily conserved signal transduction pathway called the unfolded protein response (UPR) that initially expands the ER network and upregulates protein folding capacity in order to restore homeostasis. However, if the ER damage is extensive or prolonged, cells initiate apoptosis. Mounting evidence suggests that apoptosis triggered by excessive stress on the protein folding capacity of the ER contributes to pathological cell loss in many common human degenerative diseases, including Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, type 2 diabetes, and liver cirrhosis. We are currently designing pharmacological interventions to precisely control and tune these signaling switches with small molecules to influence cell survival and prevent these diseases.
- Ghosh R, Wang L, Wang ES, Perera BGK, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schurer SC, Snapp EL, Gould DB, German MS, Backes BJ, Maly DJ, Oakes SA*, Papa FR*. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014;158:1-15. *Co-corresponding authors.
- Upton, JP, Wang L., Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA. 2012. IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science. 2012;338:818-22.
- Lerner AG, Upton JP, Tayakuniyal PP, Ghosh R, Shen S, Nakagawa Y, Nguyen V, Truisina A, Heiman M, Heintz N, Greengard P, Backes BJ, Hui S, Tang Q, Oakes SA*, Papa FR*. IRE1alpha induces thioredoxin-interacting protein (TXNIP) to activate the NLRP3 inflammasome and promote cell death. Cell Metab. 2012;16:250-64. *Co-corresponding authors.
- Austgen K, Johnson ET, Park TJ, Curran T, Oakes SA. The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress. Nat Cell Biol. 2011;14(1):87-92.
- Reyes NA, Fisher JK, Austgen K, VandenBerg S, Huang EJ, and Oakes SA. Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis. J. Clin. Invest. 2010;120(10):3673-3679.
- Han D Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, and Papa FR. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell. 2009;138, 562-575.
- 2003-2008: NIH Mentored Clinical Scientist Development Award (K08)
- 2007-2011: HHMI Early Career Physician Scientist Award
- 2012-2015: American Cancer Society Research Scholar
- 2013-2015: Harrington Discovery Institute Scholar-Innovator Award
- 2013: Inductee—American Society for Clinical Investigation (ASCI)
- Associate Professor of Pathology
- Research and Autopsy
- Phone: (415) 476-1777
- Pager: (415) 443-9454
- Fax: (415) 514-3165
- Scott A. Oakes, MD
- Pathology, Box 0511
- 513 Parnassus Avenue, Room HSW-517
- San Francisco, CA 94143
Other UCSF Organizational Association(s)
- Helen Diller Family Comprehensive Cancer Center
- Biomedical Sciences (BMS) Graduate Program
- Diabetes Center