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dc.contributor.authorAlfano, Alan
dc.date.accessioned2016-01-29T18:24:34Z
dc.date.available2017-02-06T17:03:36Z
dc.date.issued2015
dc.identifier.urihttp://hdl.handle.net/10713/5035
dc.descriptionUniversity of Maryland, Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 2015en_US
dc.description.abstractProstate cancer (PCa) is the second most lethal cancer in men, accounting for an estimated 30,000 deaths in 2013. For diagnoses of advanced disease, the standard treatment is androgen deprivation therapy (ADT). Despite initial success of ADT, many PCa patients relapse into an incurable androgen-insensitive disease termed Castration Resistant Prostate Cancer (CRPC). Taxane compounds (such as docetaxel [DTX]) + Steroid (such as Prednisone) is a first-line treatment, but DTX resistance is common in patients with advanced CRPC. Tubulins are an integral part of the cytoskeleton, and play a pivotal role in cell signaling, migration, and division. They exist in vivo either as soluble monomers or as α-/β-tubulin heterodimers. These dimers are either recycled into monomers, or polymerized into microtubules (MTs). Microtubules serve a range of functions including structural support of the cell body, scaffolding for signaling molecules, and mitotic spindle support. β-tubulin is also the molecular target for taxane compounds. High expression levels of Class III β-tubulin (TUBB3, a primarily neural isoform of β-tubulin) correlate with taxane resistance and poor prognosis in several human cancers, including ovarian cancer (serous adenocarcinoma), breast cancer, non-small-cell lung cancer (NSCLC), and prostate cancer (PCa). It is known that c-Src (a known proto-oncogene) phosphorylates β-tubulins during both hematopoietic and neural differentiation. This has also been observed in leukemia cells. Despite recent advances, the relationship between Src-mediated tyrosine phosphorylation and microtubule modulation is still poorly understood, especially in the context of advanced solid malignancies. Herein we show that activated Src-kinase is able to phosphorylate TUBB3 at tyrosine 340 (Y340), and that tyrosine phosphorylation of βIII-tubulin at Y340 by Src-family kinases is critical in stabilization of TUBB3, and also plays a role in regulation of mitotic spindles. Given the clinical utility of TUBB3 as a biomarker of poor prognosis, characterizing cancer-specific post-translational modification (PTM) of TUBB3 in aggressive cancer cell types could lead to more specified biomarkers of patient outcome or therapeutic response. Additionally, a deeper understanding of the complex interplay between the Src family of kinases (SFKs) and microtubules could enable future researchers to design more specific and effective microtubule-targeted and/or SFK-targeted therapies.en_US
dc.language.isoen_USen_US
dc.subjectSrcen_US
dc.subjectTUBB3en_US
dc.subject.lcshProstate--Canceren_US
dc.subject.meshDrug Resistanceen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshTubulinen_US
dc.titleRegulation of Class III Beta-Tubulin by Src-Mediated Tyrosine Phosphorylationen_US
dc.typedissertationen_US
dc.contributor.advisorQiu, Yun
dc.description.urinameFull Texten_US
refterms.dateFOA2019-02-21T01:14:41Z


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