Mechanisms of HIF-1⍺ Regulation in CNS Disease
Phosphatase Regulation of HIF-1-dependent transcription
De novo gene expression induced by the hypoxia-inducible factor HIF-1α regulates neuron survival under ischemic conditions. Our lab is investigating how HIF phosphorylation and transcriptional activity is modulated by members of the MAP kinase family of phosphatases (DUSPs). In addition to increasing hypo-phosphorylated forms of HIF-1α in cells, DUSP1/MKP-1 enhances proteolytic cleavage of HIF-1α at a domain near the amino-terminal transactivation domain. This endoproteolytic event generates a HIF dominant negative capable of shutting down intrinsic HIF-1 transcriptional activity in cells.
In this project, we test the hypothesis that the interaction between MKP-1 and HIF-1α and resulting endoproteolytic cleavage serves as a molecular switch providing tight regulation of genes involved in metabolism, autophagy, and apoptotic signaling. In these analyses we investigate:
- The mechanism by which MKP regulates HIF-1α post-translational modification
- The discrete modifications and factors required for HIF-1α cleavage
- The effects these changes have on neuron survival.
Together, these experiments focus on a novel, physiologically responsive signaling node that modulates HIF-1α’s latent apoptotic potential. The identification of suitable targets in this network will enable the discovery of small molecules designed to either inhibit or augment transcription-dependent injury.
Dual Specificity Phosphatases in CNS Disease
Approximately 14,000 patients are diagnosed with glioblastoma multiforme (GBM) in the United States annually, and current standard-of-care therapy including surgical resection followed by radiation and adjunctive temozolomide treatment typically results in median survival of only 12-15 months from diagnosis. These tumors are both genetically and histologically heterogeneous with many of the associated molecular defects enhance hypoxia-inducible factor-1α (HIF-1α) activity resulting in increased tumor cell growth, angiogenesis, invasion, and metabolic plasticity.
Mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1) is ubiquitously expressed and serves to inhibit HIF-1α. MKP-1 induction has been linked to chemoresistance through effects on the c-Jun N-terminal kinase pathway. However, MKP-1 induction following oxidative stress induces a pro-apoptotic effect by interrupting MAPK pro-survival signaling, and its induction in GBM exerts anti-tumor activity by reducing tumor migration and invasion.
Our lab is currently investigating the relationship between MKP-1/DUSP1 expression and HIF-1 dependent signaling in models of GBM. Our results indicate that MKP-1 activity is associated with tumor stem differentiation, regulated by anti-neoplastic agents, and exhibits anti-tumorigenic effects in vitro. We hope that further study regarding the link between MKP-1 regulation and HIF-1a activity will provide new therapeutic options for this fatal disease.
Relevant Publications & Patents
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