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Subject Reviews

Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Etty N. Benveniste, Department of Cell Biology, 1918 University Boulevard, MCLM 395A, University of Alabama at Birmingham, Birmingham, AL 35294-0005. Phone: 205-934-7667; Fax: 205-975-6748. E-mail: tika{at}uab.edu

Abstract

Glioblastoma is the most common and severe primary brain tumor in adults. Its aggressive and infiltrative nature renders the current therapeutics of surgical resection, radiation, and chemotherapy relatively ineffective. Accordingly, recent research has focused on the elucidation of various signal transduction pathways in glioblastoma, particularly aberrant activation. This review focuses on the signal transducer and activator of transcription-3 (STAT-3) signal transduction pathway in the context of this devastating tumor. STAT-3 is aberrantly activated in human glioblastoma tissues, and this activation is implicated in controlling critical cellular events thought to be involved in gliomagenesis, such as cell cycle progression, apoptosis, angiogenesis, and immune evasion. There are no reports of gain-of-function mutations in glioblastoma; rather, the activation of STAT-3 is thought to be a consequence of either dysregulation of upstream kinases or loss of endogenous inhibitors. This review provides detailed insight into the multiple mechanisms of STAT-3 activation in glioblastoma, as well as describing endogenous and chemical inhibitors of this pathway and their clinical significance. In glioblastoma, STAT-3 acts a molecular hub to link extracellular signals to transcriptional control of proliferation, cell cycle progression, and immune evasion. Because STAT-3 plays this central role in glioblastoma signal transduction, it has significant potential as a therapeutic target. (Mol Cancer Res 2008;6(5):675–84)

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