Date

May 2010

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular and Medical Genetics

Institution

Oregon Health & Science University

Abstract

Ribotoxic stressors can be defined as chemical, biological, or physical agents that: (i) inhibit translation by means of interactions with, and/or damage to, the ribosome and (ii) in doing so, provoke productive cellular responses that result in the active expression of gene products (e.g. cytokines or growth factors) that modulate the organismal response to the stressor. The responses best characterized to date involve potentiation of the JNK and p38 families of SAPKs. SAPKs are activated by upstream SAP kinase kinases (SAPKKs), which, in turn, are subject to phosphorylation and activation by SAPKKKs. ZAK is a pivotal MAP3K mediating ribotoxic stress response. For millennia, humans have been exposed to ribotoxic stressors through accidental ingestion or inhalation, or, in recent times, as occasional agents of bioterrorism. Among the known ribotoxic stressors, of greatest importance to human health are probably the Shiga toxins. Hemolytic-uremic syndrome (HUS) results from an infection by Shiga toxin (Stx)-producing Escherichia coli (STEC), most commonly serotype O157:H7, and is the most common cause of acute renal failure in children. In this thesis, I demonstrate that doxorubicin, an anthracycline drug that is one of the most effective and widely used anticancer agents for the treatment of both hematologic and solid tumors, is a novel ribotoxic stressor that inhibits protein synthesis and requires actively translating ribosomes to activate SAPKs. Numerous ribotoxic stressors play significant roles in the development of various human diseases. However, if a person is infected with a ribotoxic stressor, such as Stx, or has side effects from treatment with a ribotoxic stressor, such as doxorubicin, then care is primarily supportive without any actual directed therapies. There are experiments demonstrating that some potential inhibitors of ribotoxic stressors, such as monoclonal antibodies against Stx2 or MAPK inhibitors may be beneficial in preventing the severe inflammation and apoptosis after exposure to Stx or doxorubicin. In this thesis, I demonstrate that a monoclonal antibody against Stx2 can prevent HUS-associated lethality. In addition, I provide evidence that sorafenib and nilotinib, kinase inhibitors that have a high affinity for ZAK, prevent doxorubicin-induced proinflammatory and apoptotic responses in a normal keratinocyte cell line, but not in a cancerous cell line. Another potential therapeutic approach for blocking doxorubicin-mediated inflammation would be to interfere with IL-1β signaling by blocking it’s processing, release, or binding to IL-1 receptors. In this thesis, I demonstrate that doxorubicin activates the NALP3 inflammasome in murine BMDM leading to processing and secretion of mature IL-1β and an area for potential therapeutic intervention. In conclusion, a better understanding of which antibiotics, cancer chemotherapeutics, and toxins are ribotoxic stressors, as well as how ribotoxic stressors inhibit protein translation, signal to MAPKs, and cause apoptosis could lead to novel therapeutic interventions to treat ribotoxic stressor-mediated human disease.

Identifier

doi:10.6083/M44B2Z9W

School

School of Medicine

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