The stress response transcription factor Nrf2 is a master regulator of a battery of antioxidant and detoxification genes that promote cell survival. Classically defined as a chemoprevention factor, recent evidence has demonstrated that Nrf2 over-activation is found in many cancers and is associated with drug-/radio-resistance, enhanced cell survival, and poor patient prognosis. Therefore, it is important to understand the molecular events that regulate its activity and how perturbations in cancer can facilitate over-activation of Nrf2. Glycogen synthase kinase-3 beta (GSK3β) has emerged as a regulator of the non-canonical Nrf2 pathway by its ability to promote the degradation of Nrf2, both directly and indirectly through a mechanism involving the Src-A subfamily kinases. However, it remains ambiguous how GSK3β is regulated in the redox environment of the cell, and whether alterations in its activity can lead to increased activation of Nrf2.
Herein, it is demonstrated that oxidative stress-induced activation of the PI3K/Akt pathway results in the phosphorylation of GSK3β Ser-9, thereby inhibiting its activity. As a result, Nrf2 is able to become stabilized and induce the transcription of its defensive target genes. Subsequently, the coordinated action of the protein phosphatases PTEN, PP2A, and PP1 help to restore the activation of GSK3β, and its ability to “shut off” the Nrf2 response. Moreover, the constitutive activation of the PI3K/Akt pathway, an event commonly found in cancers, leads to a sustained inhibition of GSK3β, which consequently functions to drive Nrf2-mediated drug resistance and cell survival.
In addition to its direct inhibition of Nrf2, GSK3β also indirectly mediates the nuclear export and degradation of Nrf2 by triggering the nuclear translocation of the Src-A subfamily kinase members Src, Fyn, Yes, and Fgr. Surprisingly, the precise mechanism of how the Src-A subfamily translocates into the nucleus is unknown. In using Fyn kinase as a model, it is apparent that the Src homology 2 (SH2) and SH3 domains are necessary, however, the SH2 domain is sufficient for nuclear import due to a putative bipartite nuclear localization sequence in the SH2 domain.
In summation, this thesis provides insight into the molecular mechanisms surrounding the ability of GSK3β to inhibit Nrf2. Ultimately, we hope that the evidence presented within will provide translational applications to include the non-canonical GSK3β/Nrf2 pathway as a therapeutic target in tumors harboring over-activation of Nrf2.
|Commitee:||Fiskum, Gary, Mao, Li, Qiu, Yun, Sausville, Edward, Shapiro, Paul|
|School:||University of Maryland, Baltimore|
|School Location:||United States -- Maryland|
|Source:||DAI-B 75/05(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology, Oncology|
|Keywords:||Antioxidants, Cancer, Glycogen synthase kinase, Oxidative stress, PI 3-kinase, Signal transduction|
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